Bi-functional Molecules to Degrade Circulating Proteins

ABSTRACT

Described herein is a bi-functional compound for removing macrophage migration inhibitory factor (MIF) or immunoglobin G (IgG). Further described herein is a pharmaceutical composition which comprise these bi-functional compounds. Further described herein is a method for treating disease states and/or conditions with the compounds or the composition. The disease states and/or conditions are mediated through MIF/IgG or where MIF/IgG is a contributing factor to the development and perpetuation of diseases and/or conditions, such as autoimmune diseases and cancer, among others.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of, and claims priority to,U.S. application Ser. No. 17/046,192, filed Oct. 8, 2020, which is a 35U.S.C. § 371 national phase application from, and claims priority to,International Application No. PCT/US2019/026239, filed Apr. 8, 2019,which claims priority under 35 U.S.C. § 119(e) to U.S. ProvisionalPatent Application No. 62/655,028, filed Apr. 9, 2018 and U.S.Provisional Patent Application No. 62/788,052, filed Jan. 3, 2019, allof which applications are incorporated herein by reference in theirentireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under GM067543 awardedby National Institutes of Health and under W81XWH-13-1-0062 awarded bythe United States Army Medical Research and Material Command. Thegovernment has certain rights in the invention.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Oct. 26, 2021, isnamed “047162-7240US2(01507)_Sequence_Listing.txt” and is 5.29 kilobytesin size.

BACKGROUND

MIF is a proinflammatory pluripotent cytokine which contributes to thedevelopment and perpetuation of many diseases. These includeatherosclerosis, rheumatoid arthritis (RA), systemic lupus erythematosus(SLE), sepsis, inflammatory bowel disease (IBD), among others. Inaddition, MIF has been shown to participate in the progression ofvarious cancers, including colon cancer, prostate cancer, breast cancer,lung cancer, cervical and adenocarcinoma, among others. In pre-clinicalmodels, inhibition of MIF has been shown to attenuate symptoms and delaydisease progression in the above-mentioned diseases.

MIF and IgG significantly contribute to the pathologic process of anumber of diseases. MIF neutralizing antibodies and small molecule MIFinhibitors have been developed, where IgG is upregulated in autoimmuneand other diseases and causes untoward effects. Because MIF acts throughvarious pathways, a MIF inhibitor is sometimes required to be able tointerrupt multiple protein-protein interactions (PPIs), posing achallenge for drug development. In the case of IgG, the removal of IgGmolecules which are upregulated and contributing to autoimmune and/orother diseases is sometimes useful to inhibit and/or ameliorate theeffects of the disease state. Therefore, a novel approach where MIF orIgG can be degraded as well as inhibited can overcome this difficultyand potentially provide a more robust therapeutic response. Encouragedby preliminary results with bi-functional MIF and IgG degraders, thepresent inventors decided to further test them in clinical-relevant invivo models and potentially develop them into therapeutics that targetMIF or IgG in diseases. They also intend to use this basic bifunctionalmolecule strategy to target other circulating proteins of interest todegradation via the ASGPr.

Therefore, there is a need for molecules that can eliminate MIP and/orIgG. The present disclosure addresses this need.

BRIEF SUMMARY

In some aspects, the present disclosure is directed to bifunctionalsmall molecules which can be used to inhibit and remove MIF or IgG. Insome embodiments, the present disclosure aims to establish a generalsmall molecule strategy to target the selective degradation of MIF orIgG, which contributes to the development and perpetuation of manydiseases. In some embodiments, the bifunctional molecule constructcontains a MIF binding motif derived from known small molecule ligandsof MIF of a IgG binding motif which comprises a ligand which binds IgG.These moieties are referred to herein generically as macrophagemigration inhibitory factor binding moiety (MIFBM) or alternatively,immunoglobulin G binding moiety (IgGBM). In some embodiments, the otherend of the bifunctional molecule is a motif that binds to hepatocyteasialoglycoprotein receptor (ASGPr), which is a triantennaryN-acetylgalactosamine or other moiety as described herein. The instantspecification sometimes refer to these moieties generically asasialoglycoprotein receptor binding moiety (ASGPRBM). The motifs whichare used to provide bifunctional compounds according to someembodiments, (MIFBM or IgGBM) and (ASGPRBM), are covalently linked via alinker such as a polyethylene glycol (PEG) or other linker as describedherein with adjustable length or other linker as described herein, whichoptionally contains one or more connector molecule(s) which connects thelinker to the MIFBM or IgGBM and/or the ASGPRBM.

In some embodiments, the bifunctional compounds selectively bind to MIFor IgG in circulation and form a protein complex. When this proteincomplex passes through the liver, the asialoglycoprotein receptorbinding moiety of the molecule (ASGPRBM), such as a triantennaryN-Acetylgalactosamine or other motif as described herein, will engagethe endo-lysosomal pathway of hepatocytes through the ASGPr. As aconsequence of this mechanism, MIF or IgG is eliminated from circulationby hepatocytes, thus resulting in lowered levels of MIF or IgG with theresult being that corresponding disease symptoms are attenuated and/oreliminated from a patient or subject administered the present compounds.In certain instances, the MIF is substantially reduced or eliminated orthe compromising IgG substantially reduced, resulting in substantiallyreduced symptoms or even a cure or elimination of the disease state orcondition.

The approach pursuant to the present disclosure is inherentlyadvantageous compared to the classical antibody-based strategy to targetMIF or IgG of the prior art. The small molecule based approach of thecurrent disclosure overcomes the limitations of traditionalantibody-based strategies, including lack of oral bioavailability,low-temperature storage requirements, immunogenicity, and high-cost.

Furthermore, the compounds and methods of the present disclosure areexpected to have a more lasting effect compared to the conventionalinhibitory approach because MIF or IgG is substantially reduced oreliminated by degradation inside hepatocytes rather than simplyinhibited by reversibly blocking the protein-receptor interaction. Thebifunctional molecule construct pursuant to the present disclosure isalso versatile in the sense that different disease states and/orconditions can be targeted by inhibiting and degrading MIF or IgG. Thus,previously discovered non-inhibitory protein binders, presently oflittle value in therapy, can be potentially therapeutically useful inthese small molecules.

In certain embodiments, the present disclosure is directed to compoundswhich are useful for removing circulating proteins which are associatedwith a disease state or condition in a patient or subject according tothe general chemical structure:

wherein [MIFBM/IgGBM] is a MIF or IgG binding moiety which bindsrespectively to circulating MIF or IgG, which are related to a diseasestate and/or condition and is to be removed by the action of hepatocyteson circulating protein (in some embodiments, the compounds selectivelybind to MIF or IgG in plasma);

[ASGPRBM] is a binding moiety which binds to hepatocytes throughasialoglycoprotein receptors which are on the surface of hepatocytes,such as in a patient or subject;

each [CON] is an optional connector chemical moiety which, when present,connects directly to [MIFBM/IgGBM] or to [ASGPRBM] or connects the[LINKER] to [MIFBM/IgGBM] or to [ASGPRBM] and

[LINKER] is a chemical moiety having a valency ranging from 1 to 15,such as ranging from 1 to 10, ranging from 1 to 5 or 1, 2 or 3, whichcovalently attaches to one or more [ASGPRM] and/or [MIFBM/IgGBM] group,optionally through a [CON], including a [MULTICON] group, wherein said[LINKER] optionally itself contains one or more [CON] or [MULTICON]group(s);

k′ is an integer ranging from 1 to 15, such as ranging from 1 to 10,ranging from 1 to 5, ranging from 1 to 3 or 1, 2 or 3;

j′ is an integer ranging from 1 to 15, such as ranging from 1 to 10,ranging from 1 to 5, ranging from 1 to 3 or 1, 2 or 3;

h and h′ are each independently an integer ranging from 0 to 15, such asranging from 1 to 15, ranging from 1 to 10, ranging from 1 to 5, rangingfrom 1 to 3 or 1, 2 or 3, optionally h and/or h′ is at least 1;

i_(L) is an integer ranging from 0 to 15, such as ranging from 1 to 15,ranging from 1 to 10, ranging from 1 to 5, ranging from 1 to 3, or 1, 2or 3, optionally i_(L) is an integer ranging from 1 to 5 or 1, 2 or 3with the proviso that at least one of h, h′ and i_(L) is at least 1, or

a pharmaceutically acceptable salt, stereoisomer, solvate or polymorphthereof.

In some embodiments [MIFBM] is a moiety according to the chemicalstructure:

wherein X_(M) is —(CH₂)_(IM), —O—(CH₂)_(IM), S—(CH₂)_(IM),NR_(M)—(CH₂)_(IM), C(O)—(CH₂)_(IM)—, a polyethylene glycol (PEG) groupcontaining from 1 to 8, such as 1-4 ethylene glycol residues or a—C(O)(CH₂)_(IM)NR_(M) group;

R_(M) is H or a C₁-C₃ alkyl group which is optionally substituted withone or two hydroxyl groups;

IM is 0-6, such as 1, 2, 3 or 4, such as 1.

In some embodiments, [IgGMB] is a group according to the chemicalstructure:

wherein DNP is a 2,4-dinitrophenyl group; or

a group according to the chemical structure:

wherein Y′ is H or NO₂;

X is O, CH₂, NR¹, S(O), S(O)₂, —S(O)₂O, —OS(O)₂, or OS(O)₂O; and

R¹ is H, a C₁-C₃ alkyl group, or a —C(O)(C₁-C₃) group; or

a group according to the chemical structure:

wherein R¹ is the same as above; and

K″ is 1-5 (such as 3-5, such as 4), or

a group represented by the chemical formula:

wherein X′ is CH₂, O, N—R^(1′), or S;

R^(1′) is H or C₁-C₃ alkyl; and

Z is a bond, a monosaccharide, disaccharide, oligosaccharide, such as asugar group selected from the monosaccharides, including aldoses andketoses, and disaccharides, including those disaccharides describedherein. Monosaccharide aldoses include monosaccharides such asaldotriose (D-glyceraldehdye, among others), aldotetroses (D-erythroseand D-Threose, among others), aldopentoses, (D-ribose, D-arabinose,D-xylose, D-lyxose, among others), aldohexoses (D-allose, D-altrose,D-Glucose, D-Mannose, D-gulose, D-idose, D-galactose and D-Talose, amongothers), and the monosaccharide ketoses include monosaccharides such asketotriose (dihydroxyacetone, among others), ketotetrose (D-erythrulose,among others), ketopentose (D-ribulose and D-xylulose, among others),ketohexoses (D-Psicone, D-Fructose, D-Sorbose, D-Tagatose, amongothers), aminosugars, including galactoseamine, sialic acid,N-acetylglucosamine, among others and sulfosugars, includingsulfoquinovose, among others. Exemplary disaccharides which find use inthe present disclosure include sucrose (which may have the glucoseoptionally N-acetylated), lactose (which may have the galactose and/orthe glucose optionally N-acetylated), maltose (which may have one orboth of the glucose residues optionally N-acetylated), trehalose (whichmay have one or both of the glucose residues optionally N-acetylated),cellobiose (which may have one or both of the glucose residuesoptionally N-acetylated), kojibiose (which may have one or both of theglucose residues optionally N-acetylated), nigerose (which may have oneor both of the glucose residues optionally N-acetylated), isomaltose(which may have one or both of the glucose residues optionallyN-acetylated), β,β-trehalose (which may have one or both of the glucoseresidues optionally N-acetylated), sophorose (which may have one or bothof the glucose residues optionally N-acetylated), laminaribiose (whichmay have one or both of the glucose residues optionally N-acetylated),gentiobiose (which may have one or both of the glucose residuesoptionally N-acetylated), turanose (which may have the glucose residueoptionally N-acetylated), maltulose (which may have the glucose residueoptionally N-acetylated), palatinose (which may have the glucose residueoptionally N-acetylated), gentiobiluose (which may have the glucoseresidue optionally N-acetylated), mannobiose, melibiose (which may havethe glucose residue and/or the galactose residue optionallyN-acetylated), melibiulose (which may have the galactose residueoptionally N-acetylated), rutinose, (which may have the glucose residueoptionally N-acetylated), rutinulose and xylobiose, among others.

In some embodiments [IgGBM] is a group according to the chemicalstructure:

wherein X_(R) is O, S or NR¹; and

X_(M) is O, NR¹ or S, and

R¹ is H or a C₁-C₃ alkyl group.

In some embodiments [IgGBM] is a group according to the chemicalstructure:

wherein X″ is O, CH₂, NR¹, S; and

R¹ is H, a C₁-C₃ alkyl group or a —C(O)(C₁-C₃) group; or

wherein X^(b) is a bond, O, CH₂ or NR¹ or S; and

R¹ is the same as above; or

a group according to the chemical structure:

where R^(N02) is a dinitrophenyl group optionally linked through CH₂,S(O), S(O)₂, —S(O)₂O, —OS(O)₂, or OS(O)₂O; or

a dinitrophenyl group according to the chemical structure:

X is O, CH₂, NR¹, S(O), S(O)₂, —S(O)₂O, —OS(O)₂, or OS(O)₂O; and

R¹ is H, a C₁-C₃ alkyl group, or a —C(O)(C₁-C₃) group.

In some embodiments [IgGBM] is a group according to the chemicalstructure:

where K′″ is 1-4 (such as 2-3, such as 3), or a

a group according to a chemical structure which is set forth in FIG. 67hereof which is covalently attached to a [CON] group, a [LINKER] groupor a [ASGPRBM] group through an amine group, such as a primary orsecondary alkyl amine group which is optionally substituted on the aminegroup with a C₁-C₃ alkyl group.

In some embodiments [IgGBM] is a peptide according to the sequence (allreferences cited are incorporated by reference herein):

-   PAM (Fassina, et al., J. Mol. Recognit. 1996, 9, 564-569);-   D-PAM (Verdoliva, et al., J. Immunol. Methods, 2002, 271, 77-88);-   D-PAM-Φ (Dinon, et al. J. Mol. Recognit. 2011, 24, 1087-1094);-   TWKTSRISIF (Krook, et al., J. Immunol. Methods 1998, 221, 151-157)    SEQ ID NO:1;-   FGRLVSSIRY (Krook, et al., J. Immunol. Methods 1998, 221, 151-157)    SEQ ID NO:2;-   Fc-III (DeLano, et al., Science 2000, 287, 1279-1283);-   FcBP-1 (Kang, et al., J. Chromatogr. A 2016, 1466, 105-112);-   FcBP-2 (Dias, et al., J. Am. Chem. Soc. 2006, 128, 2726-2732);-   Fc-III-4c (Gong, et al., Bioconjug. Chem. 2016, 27, 1569-1573);-   EPIHRSTLTALL (Ehrlich, et al., J. Biochem. Biophys. Method 2001, 49,    443-454) SEQ ID NO:3;-   APAR (Camperi, et al., Biotechnol. Lett. 2003, 25, 1545-1548) SEQ ID    NO:4;-   FcRM (Fc Receptor Mimetic, Verdoliva, et al., ChemBioChem 2005, 6,    1242-1253);-   HWRGWV (Yang, et al., J. Peptide Res. 2006, 66, 110-137) SEQ ID    NO:5;-   HYFKFD (Yang, et al., J. Chromatogr. A 2009, 1216, 910-918) SEQ ID    NO: 6;-   HFRRHL (Menegatti, et al., J. Chromatogr. A 2016, 1445, 93-104) SEQ    ID NO:7;-   HWCitGWV (Menegatti, et al., J. Chromatogr. A 2016, 1445, 93-104)    SEQ ID NO:8;-   D2AAG (Small Synthetic peptide ligand, Lund, et al., J. Chromatogr.    A 2012, 1225, 158-167);-   DAAG (Small Synthetic peptide ligand, Lund, et al., J. Chromatogr. A    2012, 1225, 158-167);-   cyclo[(N—Ac)S(A)-RWHYFK-Lact-E] (Menegatti, et al., Anal. Chem.    2013, 85, 9229-9237) (SEQ ID NO:9-Lact-E);-   cyclo[(N—Ac)-Dap(A)-RWHYFK-Lact-E] (Menegatti, et al., Anal. Chem.    2013, 85, 9229-9237) (SEQ ID NO:10-Lact-E);-   cyclo[Link-M-WFRHYK] (Menegatti, et al., Biotechnol. Bioeng. 2013,    110, 857-870) SEQ ID NO:11;-   NKFRGKYK (Sugita, et al., Biochem. Eng. J. 2013, 79, 33-40) SEQ ID    NO: 12;-   NARKFYKG (Sugita, et al., Biochem. Eng. J. 2013, 79, 33-40) SEQ ID    NO: 13;-   FYWHCLDE (Zhao, et al., Biochem. Eng. J. 2014, 88, 1-11) SEQ ID NO:    14;-   FYCHWALE (Zhao, et al., J. Chromatogr. A 2014, 1355, 107-114) SEQ ID    NO: 15;-   FYCHTIDE (Zhao, et al., J. Chromatogr. A 2014, 1359, 100-111) SEQ ID    NO:16;-   Dual 1/3 (Zhao, et al., J. Chromatogr. A 2014, 1369, 64-72);-   RRGW (Tsai, et al., Anal. Chem. 2014, 86, 2931-2938) SEQ ID NO: 17;-   KHRFNKD (Yoo and Choi, BioChip J. 2015, 10, 88-94) SEQ ID NO: 18;

In some embodiments [ASGPRBM] is a group according to the chemicalstructure:

where X is 1-4 atoms in length and comprises O, S, N(R^(N1)) orC(R^(N1))(R^(N1)) groups such that

when X is 1 atom in length, X is O, S, N(R^(N1)) or C(R^(N1))(R^(N1)),

when X is 2 atoms in length, no more than 1 atom of X is O, S orN(R^(N1)),

when X is 3 or 4 atoms in length, no more than 2 atoms of X are O, S orN(R^(N1));

where R^(N1) is H or a C₁-C₃ alkyl group optionally substituted withfrom 1-3 halo groups, such as F (in some embodiments, R^(N1) is H ormethyl);

R₁ and R₃ are each independently H, —(CH₂)_(K)OH, —(CH₂)_(K)OC₁-C₄alkyl, which is optionally substituted with from 1-3 halo (F, Cl, Br, orI) groups, C₁-C₄ alkyl, which is optionally substituted with from 1-3halo (F, Cl, Br, or I) groups,

—(CH₂)_(K)vinyl, O—(CH₂)_(K)vinyl, —(CH₂)_(K)alkynyl, —(CH₂)_(K)COOH,—(CH₂)_(K)C(O)O—C₁-C₄ alkyl which is optionally substituted with from1-3 halo, such as F groups, O—C(O)—C₁-C₄ alkyl, which is optionallysubstituted with from 1-3 halo, such as F groups, —C(O)—C₁-C₄ alkyl,which is optionally substituted with from 1-3 halo, such as F groups, or

R₁ and R₃ are each independently a

group, which is optionally substituted with up to three (such as 1) halogroups (such as F), C₁-C₄ alkyl groups, each of which is optionallysubstituted with from one to three halo groups, such as F, or one or twohydroxyl groups, or O—C₁-C₄ alkyl groups, each of which alkyl groups isoptionally substituted with from one to three halo groups, such as F, orone or two hydroxyl groups, and K is independently an integer rangingfrom 0-4 (such as 0, 1, 2, 3 or 4), or

R₁ and R₃ are each independently a group according to the chemicalstructure:

where R⁷ is O—C₁-C₄ alkyl, which is optionally substituted with from 1to 3 halo groups, such as F and 1 or 2 hydroxy groups, or R⁷ is a

—NR^(N3)R^(N4) group or a

or R₁ and R₃ are each independently a group according to the structure:

group,wherein CYC is a ring selected from the group consisting of:

and C₃-C₈ saturated carbocyclic, wherein each of LINKERX, R^(C), and—(CH₂)_(K)— are attached to an open valence in CYC, including N—H;

R^(C) is absent, H, C₁-C₄ alkyl which is optionally substituted withfrom 1-3 halo (such as F) groups or 1-2 hydroxyl groups, or a groupaccording to the structure:

where R₄, R₅ and R₆ are each independently, H, halo (F, Cl, Br, I), CN,NR^(N1)R^(N2)

—(CH₂)_(K)OH, —(CH₂)_(K)OC₁-C₄ alkyl, which is optionally substitutedwith from 1-3 halo (F, Cl, Br, I) groups, C₁-C₃ alkyl, which isoptionally substituted with from 1-3 halo (F, Cl, Br, I) groups,—O—C₁-C₃-alkyl, which is optionally substituted with from 1-3 halo, suchas F groups, —(CH₂)_(K)COOH, —(CH₂)_(K)C(O)O—C₁-C₄ alkyl which isoptionally substituted with from 1-3 halo, such as F groups,O—C(O)—C₁-C₄ alkyl, which is optionally substituted with from 1-3 halo,such as F groups, —C(O)—C₁-C₄ alkyl, which is optionally substitutedwith from 1-3 halo, such as F groups, or

R^(C) is

where R^(N), R^(N1) and R^(N2) are each independently H or a C₁-C₃ alkylgroup which is optionally substituted with from one to three halogroups, such as F, or one or two hydroxyl groups;

K is independently an integer ranging from 0-4 (0, 1, 2, 3 or 4);

K′ is an integer ranging from 1-4, such as 1;

R^(N3) is H, or a C₁-C₃ alkyl group which is optionally substituted with1-3 halo groups, such as F or 1 or 2 hydroxy groups; and

R^(N4) is H, a C₁-C₃ alkyl group which is optionally substituted with1-3 halo groups, such as F or 1 or 2 hydroxy groups, or R^(N4) is a

group, where K is sometimes 1;

is a linker group which is comprises to at least one [MIFBM/IgGBM] groupand links the [MIFBM/IgGBM] group to the [ASGPRBM] through one or moreoptional [CON] groups, or

is a linker group which contains at least one or more functional groupswhich can be used to covalently bond the linker group to at least one[MIFBM/IgGBM] group or optional [CON] group;

R₂ is a

group where R^(N1) and K are the same as above;

R^(AM) is H, a C₁-C₄ alkyl group optionally substituted with up to 3halo groups (such as F) and one or two hydroxyl groups, a —(CH₂)_(K)COOHgroup, a —(CH₂)_(K)C(O)O—C₁-C₄ alkyl group which is optionallysubstituted with from 1-3 halo, such as F groups, a

O—C(O)—C₁-C₄ alkyl group, which is optionally substituted with from 1-3halo, such as F groups, a —C(O)—C₁-C₄ alkyl group, which is optionallysubstituted with from 1-3 halo, such as F groups, a—(CH₂)_(K)—NR^(N3)R^(N4) group where R^(N3) is H, or a C₁-C₃ alkyl groupwhich is optionally substituted with 1-3 halo groups, such as F or 1 or2 hydroxy groups; and

R^(N4) is H, a C₁-C₃ alkyl group which is optionally substituted with1-3 halo groups, such as F or 1 or 2 hydroxy groups, or R^(N4) is a

group (K sometimes 1), or

R₂ is a

group,

where R^(TA) is H, CN, NR^(N1)R^(N2), —(CH₂)_(K)OH, —(CH₂)_(K)OC₁-C₄alkyl, which is optionally substituted with from 1-3 halo (F, Cl, Br, orI) groups, C₁-C₄ alkyl, which is optionally substituted with from 1-3halo (F, Cl, Br, or I) groups, —(CH₂)_(K)COOH, —(CH₂)_(K)C(O)O—C₁-C₄alkyl which is optionally substituted with from 1-3 halo, such as Fgroups, O—C(O)—C₁-C₄ alkyl, which is optionally substituted with from1-3 halo, such as F groups, —C(O)—C₁-C₄ alkyl, which is optionallysubstituted with from 1-3 halo, such as F groups, or R^(TA) is a C₃-C₁₀aryl or a three- to ten-membered heteroaryl group containing up to 5heteroaryl atoms, each of said aryl or heteroaryl groups beingoptionally substituted with up to three (such as 1) CN, NR^(N1)R^(N2),—(CH₂)_(K)OH, —(CH₂)_(K)OC₁-C₄ alkyl, which is optionally substitutedwith from 1-3 halo (F, Cl, Br, or I) groups, C₁-C₃ alkyl, which isoptionally substituted with from 1-3 halo (F, Cl, Br, or I) groups or 1or 2 hydroxy groups, —O—C₁-C₃-alkyl, which is optionally substitutedwith from 1-3 halo, such as F groups, —(CH₂)_(K)COOH,—(CH₂)_(K)C(O)O—C₁-C₄ alkyl which is optionally substituted with from1-3 halo, such as F groups, O—C(O)—C₁-C₄ alkyl, which is optionallysubstituted with from 1-3 halo, such as F groups or —(CH₂)_(K)C(O)—C₁-C₄alkyl which is optionally substituted with from 1-3 halo, such as Fgroups, or

R^(TA) is

R^(TA) is a

group which is optionally substituted with up to three, such as 1 C₁-C₃alkyl groups which are optionally substituted with up to three halo(such as F) groups, or R^(TA) is a

group,

wherein R^(N), R^(N1) and R^(N2) are each independently H or a C₁-C₃alkyl group which is optionally substituted with from one to three halogroups, such as F, or one or two hydroxyl groups and

wherein each —(CH₂)_(K) group is optionally substituted with 1-4, suchas 1 or 2, C₁-C₃ alkyl groups which are optionally substituted with from1-3 fluoro groups or 1-2 hydroxyl groups;

and K is independently 0-4 (0, 1, 2, 3 or 4).

In some embodiments, [CON] is a connector moiety (including a[MULTICON]) as otherwise described herein.

In some embodiments, [LINKER] is a linking moiety as otherwise describedherein which links [MIFBM/IgGBM] to the [ASGPRBM] group and optionallycontains one or more connector moieties (which optionally connect(s)more than one chemical moiety to provide said linking moiety or whichconnects said linking moiety to said [MIFBM/IgGBM] group or said[ASGPRBM] group, or a pharmaceutically acceptable salt, stereoisomer,solvate or polymorph thereof.

In some embodiments, X is —O—C(R^(N1))(R^(N1))

-   -   C(R^(N1))(R^(N1))—O—, —S—C(R^(N1))(R^(N1)),        C(R^(N1))(R^(N1))—S—, N(R^(N1))—C(R^(N1))(R^(N1))        C(R^(N1))(R^(N1))—N(R^(N1)) or        C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)) when X is 2 atoms in length,    -   X is —O—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)),        C(R^(N1))(R^(N1))—O—C(R^(N1))(R^(N1))—, —O—C(R^(N1))(R^(N1)),        —O—C(R^(N1))(R^(N1))—S—, —O—C(R^(N1))(R^(N1))—N(R^(N1))—,        —S—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)),        C(R^(N1))(R^(N1))—S—C(R^(N1))(R^(N1))—,        C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—S, —S—C(R^(N1))(R^(N1))—S—,        —S—C(R^(N1))(R^(N1))—O—, —S—C(R^(N1))(R^(N1))—N(R^(N1))—,        N(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))        C(R^(N1))(R^(N1))—N(R^(N1))—C(R^(N1))(R^(N1)),        C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—N(R^(N1))        N(R^(N1))—C(R^(N1))(R^(N1))—N(R^(N1)) or        C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)) when X is        3 atoms in length, and    -   X is —O—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)),        C(R^(N1))(R^(N1))—O—C(R^(N1))(R^(N1))—(R^(N1))(R^(N1))—,        —O—C(R^(N1))(R^(N1))—O—C(R^(N1))(R^(N1))—,        —S—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—,        C(R^(N1))(R^(N1))—S—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—,        C(R^(N1))(R^(N1))—(R^(N1))(R^(N1))—S—C(R^(N1))(R^(N1))—,        —S—C(R^(N1))(R^(N1))—S—C(R^(N1))(R^(N1))—,        N(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—,        C(R^(N1))(R^(N1))—N(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)),        C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—N(R^(N1)),        N(R^(N1))—C(R^(N1))(R^(N1))—N(R^(N1)) or        C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)) when X is        4 atoms in length where R^(N1) is the same as above. In some        embodiments, R^(N1) is H.

In embodiments, X is OCH₂ or CH₂O. In some embodiments R^(N1) is H.

In embodiments, the [ASGPRBM] group is a group according to the chemicalstructure:

where R₁, R₂ and R₃ are the same as above, ora pharmaceutically acceptable salt, stereoisomer, solvate or polymorphthereof.

In some embodiments, the [ASGPRBM] group is a group according to thechemical structure.

where R^(A) is a C₁-C₃ alkyl group which is optionally substituted with1-5 halo (such as F) groups (In some embodiments, R^(A) is a methyl orethyl group which is optionally substituted with from 1-3 fluorogroups);

Z_(A) is —(CH₂)_(IM), —O—(CH₂)_(IM), S—(CH₂)_(IM), NR_(M)—(CH₂)_(IM),C(O)—(CH₂)_(IM)—, a PEG group containing from 1 to 8, such as 1-4ethylene glycol residues or a —C(O)(CH₂)_(IM)NR_(M) group (In someembodiments, a PEG containing group comprising from 1 to 8 ethyleneglycol, such as 2-4 ethylene glycol residues) where IM and R_(M) are thesame as above; and

Z_(B) is absent, (CH₂)_(IM), C(O)—(CH₂)_(IM)— or C(O)—(CH₂)_(IM)—NR_(M),where IM and R_(M) are the same as above.

In some embodiments, R₁ and R₃ are each independently often a groupaccording to the chemical structure:

where R^(C),

and K are the same as above.

In some embodiments, in the above-described compounds,

where R^(C),

and K are the same as above.

In some embodiments, the compounds include the compounds which arepresented in FIGS. 1, 7 and 13 . In some embodiments, additionalcompounds are presented in FIGS. 16-66 and include final compounds setforth therein and intermediates which are used to make final compoundspursuant to the present disclosure.

In some embodiments, R₁ and R₃ of the [ASGPRBM] group include thosemoieties which are presented in FIG. 68 hereof. In some embodiments, R₂of the [ASGPRBM] group include those moieties which are presented inFIG. 69 hereof.

In some embodiments, the IgGBM group is a FCIII group according to thechemical structure:

FCIII, which can be represented as

or a FcIII-4c peptide represented as

In some aspects, the present disclosure is directed to a pharmaceuticalcomposition comprising an effective amount of a compound according tothe present disclosure in combination with a pharmaceutically acceptablecarrier, additive or excipient, optionally in combination with at leastone additional bioactive agent.

In some aspects, the present disclosure is directed to a method oftreating a disease state or condition where MIF is related to orcontributes to a disease state and or condition or the symptomologyassociated with the disease state or condition. These disease statesand/or conditions include, autoimmune diseases and numerous inflammatorydiseases for example, rheumatoid arthritis (RA), systemic lupuserythematosus (SLE), Alzheimer's disease, atherosclerosis, heartdisease, stroke and cancer (including leukemia), among numerous others.In some embodiments, the method of treatment comprises administering toa patient or subject in need of therapy an effective amount of at leastone compound according to the present disclosure, optionally incombination with an additional bioactive agent to reduce the likelihoodof, inhibit and/or treat the disease state or condition by removing MIFassociated with the disease state and/or condition from the circulationof the patient or subject.

In experiments, bi-functional molecules of the present disclosure,MIF-GN₃ were able to induce the degradation of human MIF injected inmice. Additional work focuses on the evaluation of MIF-GN₃ in autoimmunedisease models as well as seeking to optimize the bi-functional MIFdegrader using different MIF and ASGPr ligands. IgG-targeting moleculeswere able to recapitulate our results with MIF in cell culture andmediated the removal of IgG from mouse serum. Thus, the presentdisclosure provides a useful platform for the development of newtherapeutics for these critical diseases.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows representative compounds according to some embodiments.Note that the figure discloses compound 3w (negative control for MIFinhibition), MIF-NVS-PEGnGN3, MIFGN3, MIF-PEGnGN3, MIF-AcF3-1,MIF-AcF3-2 and MIF-AcF3-3. Note that n in the PEG linker sometimesranges from 1-12, such as 1 to 10, 2 to 8, 2 to 6, 2 to 5 or 1, 2, 3 or4.

FIG. 2 shows fluorescence polarization data of MIF-FITC binding to humanMIF, indicating that our MIF-binding moiety binds MIF, in accordancewith some embodiments. Bifunctional molecules WJ-PEG4-GN3, WJ-PEG2-GN3,and NVS-PEG3-GN3 bound competitively with MIF-FITC, indicating that thebifunctional molecules maintain the ability to bind human MIF.

FIG. 3 shows that bifunctional molecules are able to deplete human MIFfrom the supernatant of culture HepG2 cells, in accordance with someembodiments.

FIG. 4 shows that MIF internalized by HepG2 cells is trafficked tolysosomes, in accordance with some embodiments.

FIG. 5 shows that MIF-GN3 mediates the depletion of injected human MIFfrom mice, in accordance with some embodiments.

FIG. 6 shows that MIF-GN3 is able to delay tumor growth in a mouse modelof prostate cancer, in accordance with some embodiments.

FIG. 7 shows molecules DNP-GN3 and DNP-AcF3-3, which are bifunctionalmolecules that bind to anti-DNP IgG and ASGPR, in accordance with someembodiments.

FIG. 8 shows that DNP-GN3 and DNP-AcF3-3 mediate the formation of aternary complex between HepG2 cells and anti-DNP, in accordance withsome embodiments.

FIG. 9 shows that DNP-GN3 and DNP-AcF3-3 mediate the uptake of alexa488-labeled anti-DNP by HepG2 cells, in accordance with someembodiments.

FIG. 10 shows that DNP-GN3 and DNP-AcF3-3 mediate the localization ofalexa 568 labeled anti-DNP to late endosomes and lysosomes, inaccordance with some embodiments.

FIG. 11 shows that DNP-AcF3-3 mediates the degradation of alexa488-labeled anti-DNP in HepG2 cells, in accordance with someembodiments.

FIG. 12 shows that DNP-GN3 mediates the depletion of anti-DNP from mouseserum, in accordance with some embodiments.

FIG. 13 shows the structures of IgG-degrading molecules IBA-GN3,Triazine-GN3, FcIII-GN3, and FcIII-4c-GN3, in accordance with someembodiments.

FIG. 14 shows that FcIII-GN3 mediates the uptake of human IgG into HepG2cells, in accordance with some embodiments. Experiment performed asdescribed above.

FIG. 15 shows that FcIII-GN3 mediates the localization of IgG to lateendosomes in HepG2 cells, in accordance with some embodiments.Experiment performed as described above.

FIGS. 16-18 show the synthesis of PEG linkers used in several molecules,in accordance with some embodiments.

FIGS. 19-21 show the synthesis of ASGPR-binding precursors and ligandsused in several molecules, in accordance with some embodiments.

FIGS. 22-26 show the synthesis of valency linkers used in severalmolecules, in accordance with some embodiments.

FIGS. 27-28 show the synthesis of MIF ligands used in severalbifunctional molecules, in accordance with some embodiments.

FIG. 29 describes the synthesis of the bifunctional moleculeMIF-NVS-PEGn-GN3, in accordance with some embodiments.

FIG. 30 describes the synthesis of bifunctional molecules MIF-GN3 andMIF-PEGn-GN3, in accordance with some embodiments.

FIG. 31 describes the synthesis of the bifunctional molecule targetingMIF and ASGPR, containing one bicyclic ASGPR AcF3 ligands, in accordancewith some embodiments.

FIG. 32 describes the synthesis of the bifunctional molecule targetingMIF and ASGPR, containing two bicyclic ASGPr AcF3 ligands, in accordancewith some embodiments.

FIG. 33 describes the synthesis of the bifunctional molecule targetingMIF and ASGPR, containing three bicyclic ASGPr ligands, in accordancewith some embodiments.

FIG. 34 shows the synthesis of DNP-GN3, in accordance with someembodiments.

FIG. 35 shows the synthesis of DNP-AcF3-3, in accordance with someembodiments.

FIG. 36 shows the synthetic scheme used to obtain IBA-GN3, in accordancewith some embodiments.

FIG. 37 shows the synthesis of triazine-GN3, in accordance with someembodiments.

FIG. 38 shows the synthetic scheme used to access FcIII-GN3, inaccordance with some embodiments.

FIG. 39 shows the synthetic scheme used to access FcIII-4c-GN3, inaccordance with some embodiments.

FIGS. 40-43 describe the synthesis of bifunctional molecules targetingMIF and ASGPr, containing three bicyclic ASGPR ligands with differentsubstitutions on the 2-amine of the sugar, in accordance with someembodiments.

FIG. 44 shows the synthesis of compound MIF-18-3, in accordance withsome embodiments.

FIG. 45 shows the synthesis of compound MIF-31-3, in accordance withsome embodiments.

FIG. 46 shows the synthesis of compound MIF-15-3, in accordance withsome embodiments.

FIG. 47 shows the synthesis of compound MIF-19-3, in accordance withsome embodiments.

FIG. 48 shows the synthesis of compound MIF-16-3, in accordance withsome embodiments.

FIG. 49 shows the synthesis of compound MIF-20-3, in accordance withsome embodiments.

FIG. 50 shows the synthesis of compound MIF-14-3, in accordance withsome embodiments.

FIG. 51 shows the synthesis of compound MIF-21-3, in accordance withsome embodiments.

FIGS. 52-66 show the synthesis of a number of MIF-binding compounds withvarious ASGPRBM moieties, in accordance with some embodiments.

FIG. 67 shows exemplary IgGBM groups each of which is covalentlyattached to a [CON] group, a [LINKER] group or a [ASGPRBM] group throughan amine group, such as a primary or secondary alkyl amine group whichis optionally substituted on the amine group with a C₁-C₃ alkyl group,in accordance with some embodiments.

FIG. 68 shows exemplary R₁ and R₃ substituents on ASGPRBM groups, inaccordance with some embodiments.

FIG. 69 shows exemplary R₂ substituents on ASGPRBM groups, in accordancewith some embodiments.

DETAILED DESCRIPTION

In some aspects, the present disclosure provides bi-functional moleculesthat utilize the endo-lysosomal machinery in the liver to eliminate MIFand/or IgG. In some embodiments, the present disclosure utilizesbi-functional molecules to target MIF or IgG and is modular andversatile. This offers convenience to apply medicinal chemistry tooptimize the molecules. For example, in preliminary experiments,incorporation of more optimized ASGPr binding motifs have been shown toenhance MIF or IgG degradation in vitro. Since the bi-functionalmolecule is capable of degrading MIF or IgG, it does not require theMIF-binding motif (MIFBM) or the IgG binding moiety (IgGBM) to be aninhibitor, but in practice many of these binders will function asinhibitors of MIF or IgG. The reality of this dual inhibitory actionopens up opportunity for the development of potent MIF or IgG binders,which might have been overlooked before for not being able to inhibitvarious PPIs. Compared to monoclonal antibodies, the small moleculeapproach of the present disclosure enables simpler, cheaper and moreconsistent manufacturing practices and provides for a therapeuticapproach with fewer potential immugenic side effects.

In some aspects, the present disclosure is directed to bi-functionalcompounds which find use as pharmaceutical agents in the treatment ofdisease states and/or conditions which are mediated through macrophagemigration inhibitory factor (MIF) or Immunoglobulin G (IgG). In someaspects, the present disclosure is directed to pharmaceuticalcompositions which comprise these bi-functional compounds as well asmethods for treating disease states and/or conditions which are mediatedthrough MIF or IgG or where MIF and IgG are contributing factors to thedevelopment and perpetuation of diseases and/or conditions, especiallyincluding autoimmune diseases and cancer, among others. In some aspects,present disclosure provides a molecular strategy to lower plasma MIFlevel or IgG levels in patients with autoimmune diseases or certaintypes of cancers and other diseases. The bi-functional moleculeconstruct is comprised of a MIF-targeting motif that is derived fromsmall molecule MIF ligands or an IgG-binding motif which binds to IgG,and an ASGPr-targeting motif that binds to hepatocyte asialoglycoproteinreceptor (ASGPr). The compounds selectively bind MIF or IgG in plasmaand subsequently engage the endo-lysosomal pathway of hepatocytesthrough ASGPr. As a consequence, MIF or IgG is internalized and degradedby hepatocytes, thus resulting in potential attenuation of correspondingdisease symptoms which are modulated through MIF and/or IgG.

In accordance with some embodiments, conventional chemical synthetic andpharmaceutical formulation methods, as well as pharmacology, molecularbiology, microbiology, and recombinant DNA techniques within the skillof the art are employed. Such techniques are well-known and areotherwise explained fully in the literature.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise (such as in the case of a groupcontaining a number of carbon atoms), between the upper and lower limitof that range and any other stated or intervening value in that statedrange is encompassed within the disclosure. The upper and lower limitsof these smaller ranges may independently be included in the smallerranges is also encompassed within the disclosure, subject to anyspecifically excluded limit in the stated range. Where the stated rangeincludes one or both of the limits, ranges excluding either both ofthose included limits are also included in the disclosure.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present disclosure, someexemplary methods and materials are now described.

It is to be noted that as used herein and in the appended claims, thesingular forms “a,” “an”, “and” and “the” include plural referencesunless the context clearly dictates otherwise.

Furthermore, the following terms shall have the definitions set outbelow. It is understood that in the event a specific term is not definedhereinbelow, that term shall have a meaning within its typical usewithin context by those of ordinary skill in the art.

Definition

The term “compound”, as used herein, unless otherwise indicated, refersto any specific chemical compound disclosed herein and includestautomers, regioisomers, geometric isomers, stereoisomers and whereapplicable, optical isomers (enantiomers) thereof, as well aspharmaceutically acceptable salts and derivatives (including prodrugforms) thereof. Within its use in context, the term compound generallyrefers to a single compound, but also may include other compounds suchas stereoisomers, regioisomers and/or optical isomers (including racemicmixtures) as well as specific enantiomers or enantiomerically enrichedmixtures of disclosed compounds. The term also refers, within context,to prodrug forms of compounds which have been modified to facilitate theadministration and delivery of compounds to a site of activity. It isnoted that in describing the present compounds, numerous substituents,linkers and connector molecules and variables associated with same,among others, are described. The use of a bond presented as -----signifies that a single bond is present or absent, depending on thecontext of the chemistry described, including the attachment of the bondto another moiety. The use of a bond presented as

signifies that a single bond or a double bond is intended depending onthe context of the chemistry described. It is understood by those ofordinary skill that molecules which are described herein are stablecompounds as generally described hereunder.

The term “patient” or “subject” is used throughout the specificationwithin context to describe an animal, generally a mammal, such as ahuman, to whom treatment, including prophylactic treatment (prophylaxis,including especially as that term is used with respect to reducing thelikelihood of metastasis of an existing cancer), with the compositionsaccording to the present disclosure is provided. For treatment of thoseinfections, conditions or disease states which are specific for aspecific animal such as a human patient or a patient of a particulargender, such as a human male or female patient, the term patient refersto that specific animal. Compounds according to the present disclosureare useful for the treatment of numerous disease states includingautoimmune disease states and/or conditions and inflammatory diseasestates and/or conditions as well as cancer, including especially for usein reducing the likelihood of metastasis or recurrence of a cancer.

The term “effective” is used herein, unless otherwise indicated, todescribe an amount of a compound or composition which, in context, isused to produce or effect an intended result, whether that resultrelates to the inhibition of the effects of a disease state (e.g. anautoimmune disease such as rheumatoid arthritis (RA) or systemic lupuserythematosus (SLE), among others, atherosclerosis, heart disease orstroke, among numerous others or a cancer, including leukemia) on asubject or the treatment or prophylaxis of a subject for secondaryconditions, disease states or manifestations of disease states asotherwise described herein. This term subsumes all other effectiveamount or effective concentration terms (including the term“therapeutically effective”) which are otherwise described in thepresent application.

The terms “treat”, “treating”, and “treatment”, etc., as used herein,refer to any action providing a benefit to a patient at risk for adisease state or condition for which a MIF protein may be removed, suchas an autoimmune disease including rheumatoid arthritis (RA) or systemiclupus erythematosus (SLE), among others, atherosclerosis, heart disease,stroke and cancer (including leukemia) including recurrence and/ormetastasis of cancer, improvement in the condition through lessening orsuppression of at least one symptom of the disease state or condition,inhibition of one or more manifestations of the disease state (e.g.,plaque formation, heart disease, cancer growth, reduction in cancercells or tissue), prevention, reduction in the likelihood or delay inprogression of a disease state or condition or manifestation of thedisease state or condition, especially including plaque formation inatheroslerosis, deterioration of tissue and inflammation in rheumatoidarthritis, further damage to cardiovascular tissue in heart disease,further damage to central nervous tissue in stroke, cancer, itsrecurrence or metastasis of the cancer, prevention or delay in the onsetof disease states or conditions which occur secondary to the diseasestate or condition including cancer recurrence or metastasis, amongothers. Treatment, as used herein, encompasses both prophylactic andtherapeutic treatment, depending on the context of the treatment. Theterm “prophylactic” when used, means to reduce the likelihood of anoccurrence or the severity of an occurrence within the context oftreatment of disease state or condition, as otherwise describedhereinabove.

As used in this application, the terms “about” and “approximately” areused as equivalents. Any numerals used in this application with orwithout about/approximately are meant to cover any normal fluctuationsappreciated by one of ordinary skill in the relevant.

The term “macrophage migration inhibitory factor binding moiety” or“MIFBM” refers to a chemical moiety on one end of the bifunctionalcompounds according to the present disclosure which is capable ofbinding to a circulating MIF protein which is associated with orcontributes to a disease state or condition as otherwise describedherein. In the present disclosure, the MIFBM is capable of binding tothe circulating MIF protein, forming a complex with the presentcompounds, and delivering the bound protein to a hepatocyte whereuponthe other end of the bifunctional molecule which contains anasialoglycoprotein receptor binding moiety (ASGPRBM) and can bind to thesurface of a hepatocyte, respectively. Once attached to the hepatocyte,the bifunctional molecule to which is bound circulating protein isinternalized by the hepatocyte through an endocytosis mechanismwhereupon the cell will destroy the protein via a lysosomal degradationor other degradation pathway. The term “immunoglobulin G binding moiety”or “IgGBM” is used to describe a moiety which binds to circulating IgGimmunoglobulin, forming a complex with bifunctional molecules accordingto the present disclosure to be ultimately destroyed in hepatocytes. Incertain instances in describing the present disclosure, the terms MIFBMand IgGBM are used synonymously.

Exemplary MIFBMs for inclusion in bifunctional compounds according tothe present disclosure include moieties found in bifunctional chemicalstructures which appear in FIG. 1 , attached hereto. In someembodiments, MIFBMs include moieties according to the chemicalstructures:

wherein X_(M) is —(CH₂)_(IM), —O—(CH₂)_(IM), S—(CH₂)_(IM),NR_(M)—(CH₂)_(IM), C(O)—(CH₂)_(IM)—, a PEG group containing from 1 to 8,such as 1-4 ethylene glycol residues or a —C(O)(CH₂)_(IM)NR_(M) group;

R_(M) is H or a C₁-C₃ alkyl group which is optionally substituted withone or two hydroxyl groups; and

IM is 0-6, such as 1, 2, 3 or 4.

The term “asialoglycoprotein receptor binding moiety” (“ASGPRBM”) refersto a binding moiety which binds to hepatocyte asialoglycoproteinreceptor. This binding moiety is also a component of the presentlyclaimed bifunctional compounds bound to the MIHBM moiety through alinker. The ASGPRBM selectively binds to hepatocyte asialoglycoproteinreceptor on the surface of hepatocytes. It is through this moiety thatbifunctional compounds complexed with circulating protein bind tohepatocytes. Once bound to the hepatocyte, the circulating MIF proteinis taken into the hepatocytes via a phagocytosis mechanism wherein thecirculating protein is degraded through lysosomal degradation.

Exemplary ASGPRBM groups for use in compounds according to the presentdisclosure, among others, include moieties according to the chemicalstructures:

where X is 1-4 atoms in length and comprises O, S, N(R^(N1)) orC(R^(N1))(R^(N1)) groups such that

when X is 1 atom in length, X is O, S, N(R^(N1)) or C(R^(N1))(R^(N1)),

when X is 2 atoms in length, no more than 1 atom of X is O, S orN(R^(N1)),

when X is 3 or 4 atoms in length, no more than 2 atoms of X are O, S orN(R^(N1));

where R^(N1) is H or a C₁-C₃ alkyl group optionally substituted withfrom 1-3 halo groups, such as F (in some embodiments, R^(N1) is H ormethyl);

R₁ and R₃ are each independently H, —(CH₂)_(K)OH, —(CH₂)_(K)OC₁-C₄alkyl, which is optionally substituted with from 1-3 halo (F, Cl, Br, orI) groups, C₁-C₄ alkyl, which is optionally substituted with from 1-3halo (F, Cl, Br, or I) groups,

—(CH₂)_(K)vinyl, O—(CH₂)_(K)vinyl, —(CH₂)_(K)alkynyl, —(CH₂)_(K)COOH,—(CH₂)_(K)C(O)O—C₁-C₄ alkyl which is optionally substituted with from1-3 halo, such as F groups, O—C(O)—C₁-C₄ alkyl, which is optionallysubstituted with from 1-3 halo, such as F groups, —C(O)—C₁-C₄ alkyl,which is optionally substituted with from 1-3 halo, such as F groups, or

R₁ and R₃ are each independently a

group, which is optionally substituted with up to three (such as 1) halogroups (such as F), C₁-C₄ alkyl groups, each of which is optionallysubstituted with from one to three halo groups, such as F, or one or twohydroxyl groups, or O—C₁-C₄ alkyl groups, each of which alkyl groups isoptionally substituted with from one to three halo groups, such as F, orone or two hydroxyl groups, and K is independently an integer rangingfrom 0 to 4 (0, 1, 2, 3 or 4), or

R₁ and R₃ are each independently a group according to the chemicalstructure:

where R⁷ is O—C₁-C₄ alkyl, which is optionally substituted with from 1to 3 halo groups, such as F and 1 or 2 hydroxy groups, or R⁷ is a

—NR^(N3)R^(N4) group or a

or R₁ and R₃ are each independently a group according to t e structure:

group,wherein CYC is a ring selected from the group consisting of:

and C₃-C₈ saturated carbocyclic, wherein each of LINKERX, R^(C), and—(CH₂)_(K)— are attached to an open valence in CYC, including N—H;

R^(C) is absent, H, C₁-C₄ alkyl which is optionally substituted withfrom 1-3 halo (such as fluoro) groups or 1-2 hydroxyl groups, or a groupaccording to the structure:

where R₄, R₅ and R₆ are each independently, H, halo (F, Cl, Br, I), CN,NR^(N1)R^(N2),

—(CH₂)_(K)OH, —(CH₂)_(K)OC₁-C₄ alkyl, which is optionally substitutedwith from 1-3 halo (F, Cl, Br, or I) groups, C₁-C₃ alkyl, which isoptionally substituted with from 1-3 halo (F, Cl, Br, or I) groups,—O—C₁-C₃-alkyl, which is optionally substituted with from 1-3 halo, suchas F groups, —(CH₂)_(K)COOH, —(CH₂)_(K)C(O)O—C₁-C₄ alkyl which isoptionally substituted with from 1-3 halo, such as F groups,O—C(O)—C₁-C₄ alkyl, which is optionally substituted with from 1-3 halo,such as F groups, —C(O)—C₁-C₄ alkyl, which is optionally substitutedwith from 1-3 halo, such as F groups, or

R^(C) is

where R^(N), R^(N1) and R^(N2) are each independently H or a C₁-C₃ alkylgroup which is optionally substituted with from one to three halogroups, such as F, or one or two hydroxyl groups;

K is independently an integer ranging from 0 to 4 (0, 1, 2, 3 or 4);

K′ is an integer ranging from 1-4, such as 1;

R^(N3) is H, or a C₁-C₃ alkyl group which is optionally substituted with1-3 halo groups, such as F or 1 or 2 hydroxy groups; and

R^(N4) is H, a C₁-C₃ alkyl group which is optionally substituted with1-3 halo groups, such as F or 1 or 2 hydroxy groups, or R^(N4) is a

group, where K is sometimes 1;

is a linker group which is comprises to at least one [MIFBM/IgGBM] groupand links the [MIFBM/IgGBM] group to the [ASGPRBM] through one or moreoptional [CON] groups, or

is a linker group which contains at least one or more functional groupswhich can be used to covalently bond the linker group to at least one[MIFBM/IgGBM] group or optional [CON] group;

R₂ is a

group where R^(N1) and K are the same as above;

R^(AM) is H, a C₁-C₄ alkyl group optionally substituted with up to 3halo groups (such as F) and one or two hydroxyl groups, a —(CH₂)_(K)COOHgroup, a —(CH₂)_(K)C(O)O—C₁-C₄ alkyl group which is optionallysubstituted with from 1-3 halo, such as F groups, a

O—C(O)—C₁-C₄ alkyl group, which is optionally substituted with from 1-3halo, such as F groups, a —C(O)—C₁-C₄ alkyl group, which is optionallysubstituted with from 1-3 halo, such as F groups, a—(CH₂)_(K)—NR^(N3)R^(N4) group where R^(N3) is H, or a C₁-C₃ alkyl groupwhich is optionally substituted with 1-3 halo groups, such as F or 1 or2 hydroxy groups; and

R^(N4) is H, a C₁-C₃ alkyl group which is optionally substituted with1-3 halo groups, such as F or 1 or 2 hydroxy groups, or R^(N4) is a

group (K is sometimes 1), or

R₂ is a

group,

where R^(TA) is H, CN, NR^(N1)R^(N2), —(CH₂)_(K)OH, —(CH₂)_(K)OC₁-C₄alkyl, which is optionally substituted with from 1-3 halo (F, Cl, Br, orI) groups, C₁-C₄ alkyl, which is optionally substituted with from 1-3halo (F, Cl, Br, or I) groups, —(CH₂)_(K)COOH, —(CH₂)_(K)C(O)O—C₁-C₄alkyl which is optionally substituted with from 1-3 halo, such as Fgroups, O—C(O)—C₁-C₄ alkyl, which is optionally substituted with from1-3 halo, such as F groups, —C(O)—C₁-C₄ alkyl, which is optionallysubstituted with from 1-3 halo, such as F groups, or R^(TA) is a C₃-C₁₀aryl or a three- to ten-membered heteroaryl group containing up to 5heteroaryl atoms, each of said aryl or heteroaryl groups beingoptionally substituted with up to three (such as 1) CN, NR^(N1)R^(N2),—(CH₂)_(K)OH, —(CH₂)_(K)OC₁-C₄ alkyl, which is optionally substitutedwith from 1-3 halo (F, Cl, Br, or I) groups, C₁-C₃ alkyl, which isoptionally substituted with from 1-3 halo (F, Cl, Br, or I) groups or 1or 2 hydroxy groups, —O—C₁-C₃-alkyl, which is optionally substitutedwith from 1-3 halo, such as F groups, —(CH₂)_(K)COOH,—(CH₂)_(K)C(O)O—C₁-C₄ alkyl which is optionally substituted with from1-3 halo, such as F groups, O—C(O)—C₁-C₄ alkyl, which is optionallysubstituted with from 1-3 halo, such as F groups or —(CH₂)_(K)C(O)—C₁-C₄alkyl which is optionally substituted with from 1-3 halo, such as Fgroups, or R^(TA) is

(in some embodiments, R^(TA) is a

group which is optionally substituted with up to three, such as 1 C₁-C₃alkyl groups which are optionally substituted with up to three halo(such as F) groups, or R^(TA) is a

group)

wherein R^(N), R^(N1) and R^(N2) are each independently H or a C₁-C₃alkyl group which is optionally substituted with from one to three halogroups, such as F, or one or two hydroxyl groups and

wherein each —(CH₂)_(K) group is optionally substituted with 1-4, suchas 1 or 2, C₁-C₃ alkyl groups which are optionally substituted with from1-3 fluoro groups or 1-2 hydroxyl groups;

and K is independently 0-4 (0, 1, 2, 3 or 4).

In some embodiments, [CON] is a connector moiety (including a[MULTICON]) as otherwise described herein.

In some embodiments, [LINKER] is a linking moiety as otherwise describedherein which links [MIFBM/IgGBM] to the [ASGPRBM] group and optionallycontains one or more connector moieties (which optionally connect(s)more than one chemical moiety to provide said linking moiety or whichconnects said linking moiety to said [MIFBM/IgGBM] group or said[ASGPRBM] group, or a pharmaceutically acceptable salt, stereoisomer,solvate or polymorph thereof.

In some embodiments, X is —O—C(R^(N1))(R^(N1))

-   -   C(R^(N1))(R^(N1))—O—, —S—C(R^(N1))(R^(N1)),        C(R^(N1))(R^(N1))—S—, N(R^(N1))—C(R^(N1))(R^(N1))        C(R^(N1))(R^(N1))—N(R^(N1)) or        C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)) when X is 2 atoms in length,    -   X is —O—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)),        C(R^(N1))(R^(N1))—O—C(R^(N1))(R^(N1))—, —O—C(R^(N1))(R^(N1))—O—,        —O—C(R^(N1))(R^(N1))—S—, —O—C(R^(N1))(R^(N1))—N(R^(N1))—,        —S—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)),        C(R^(N1))(R^(N1))—S—C(R^(N1))(R^(N1))—,        C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—S, —S—C(R^(N1))(R^(N1))—S—,        —S—C(R^(N1))(R^(N1))—O—, —S—C(R^(N1))(R^(N1))—N(R^(N1))—,        N(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)),        C(R^(N1))(R^(N1))—N(R^(N1))—C(R^(N1))(R^(N1)),        C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—N(R^(N1)),        N(R^(N1))—C(R^(N1))(R^(N1))—N(R^(N1)) or        C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)) when X is        3 atoms in length, and    -   X is —O—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)),        C(R^(N1))(R^(N1))—O—C(R^(N1))(R^(N1))—(R^(N1))(R^(N1))—,        —O—C(R^(N1))(R^(N1))—O—C(R^(N1))(R^(N1))—,        —S—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—,        C(R^(N1))(R^(N1))—S—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—,        C(R^(N1))(R^(N1))—(R^(N1))(R^(N1))—S—C(R^(N1))(R^(N1))—,        —S—C(R^(N1))(R^(N1))—S—C(R^(N1))(R^(N1))—,        N(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—,        C(R^(N1))(R^(N1))—N(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)),        C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—N(R^(N1))        N(R^(N1))—C(R^(N1))(R^(N1))—N(R^(N1)) or        C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)) when X is        4 atoms in length where R^(N1) is the same as above. Most often,        R^(N1) is H.

In some embodiments, X is OCH₂ or CH₂O. In some embodiments, R^(N1) isH.

In embodiments, the [ASGPRBM] group is a group according to the chemicalstructure:

where R₁, R₂ and R₃ are the same as above, or

a pharmaceutically acceptable salt, stereoisomer, solvate or polymorphthereof.

In embodiments, the [ASGPRBM] group is a group according to the chemicalstructure:

where R^(A) is a C₁-C₃ alkyl group which is optionally substituted with1-5 halo (such as fluoro) groups (in some embodiments, R^(A) is a methylor ethyl group which is optionally substituted with from 1-3 fluorogroups);

Z_(A) is —(CH₂)_(IM), —O—(CH₂)_(IM), S—(CH₂)_(IM), NR_(M)—(CH₂)_(IM),C(O)—(CH₂)_(IM)—, a polyethylene glycol (PEG) group containing from 1 to8, such as 1-4 ethylene glycol residues or a —C(O)(CH₂)_(IM)NR_(M) group(such as a PEG containing group comprising from 1 to 8 ethylene glycol,such as 2-4 ethylene glycol residues) where IM and R_(M) are the same asabove; and

Z_(B) is absent, (CH₂)_(IM), C(O)—(CH₂)_(IM)— or C(O)—(CH₂)_(IM)—NR_(M),where IM and R_(M) are the same as above.

In some embodiments, ASPGRM group set forth above is represented asfollows:

The term “neoplasia” or “cancer” is used throughout the specification torefer to the pathological process that results in the formation andgrowth of a cancerous or malignant neoplasm, i.e., abnormal tissue thatgrows by cellular proliferation, often more rapidly than normal andcontinues to grow after the stimuli that initiated the new growth cease.Malignant neoplasms show partial or complete lack of structuralorganization and functional coordination with the normal tissue and mostinvade surrounding tissues, metastasize to several sites, and are likelyto recur after attempted removal and to cause the death of the patientunless adequately treated. As used herein, the term neoplasia is used todescribe all cancerous disease states and embraces or encompasses thepathological process associated with malignant hematogenous, ascitic andsolid tumors. Neoplasms include, without limitation, morphologicalirregularities in cells in tissue of a subject or host, as well aspathologic proliferation of cells in tissue of a subject, as comparedwith normal proliferation in the same type of tissue. Additionally,neoplasms include benign tumors and malignant tumors (e.g., colontumors) that are either invasive or noninvasive. Malignant neoplasms(cancer) are distinguished from benign neoplasms in that the former showa greater degree of anaplasia, or loss of differentiation andorientation of cells, and have the properties of invasion andmetastasis. Examples of neoplasms or neoplasias from which the targetcell of the present disclosure may be derived include, withoutlimitation, carcinomas (e.g., squamous-cell carcinomas, adenocarcinomas,hepatocellular carcinomas, and renal cell carcinomas), particularlythose of the bladder, bowel, breast, cervix, colon, esophagus, head,kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach;leukemias; benign and malignant lymphomas, particularly Burkitt'slymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas;myeloproliferative diseases; sarcomas, particularly Ewing's sarcoma,hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheralneuroepithelioma, and synovial sarcoma; tumors of the central nervoussystem (e.g., gliomas, astrocytomas, oligodendrogliomas, ependymomas,gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas,medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas,neurofibromas, and Schwannomas); germ-line tumors (e.g., bowel cancer,breast cancer, prostate cancer, cervical cancer, uterine cancer, lungcancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma,esophageal cancer, pancreatic cancer, stomach cancer, liver cancer,colon cancer, and melanoma); mixed types of neoplasias, particularlycarcinosarcoma and Hodgkin's disease; and tumors of mixed origin, suchas Wilms' tumor and teratocarcinomas (Beers and Berkow (eds.), The MerckManual of Diagnosis and Therapy, 17.sup.th ed. (Whitehouse Station,N.J.: Merck Research Laboratories, 1999) 973-74, 976, 986, 988, 991).All of these neoplasms may be treated using compounds according to thepresent disclosure.

Representative common cancers to be treated with compounds according tothe present disclosure include, for example, prostate cancer, metastaticprostate cancer, stomach, colon, rectal, liver, pancreatic, lung,breast, cervix uteri, corpus uteri, ovary, testis, bladder, renal,brain/CNS, head and neck, throat, Hodgkin's disease, non-Hodgkin'slymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skincancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing'ssarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma,Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx,oesophagus, larynx, kidney cancer and lymphoma, among others, which maybe treated by one or more compounds according to the present disclosure.Because of the activity of the present compounds, the present disclosurehas general applicability treating virtually any cancer in any tissue,thus the compounds, compositions and methods of the present disclosureare generally applicable to the treatment of cancer and in reducing thelikelihood of development of cancer and/or the metastasis of an existingcancer.

In certain particular aspects of the present disclosure, the cancerwhich is treated is metastatic cancer, a recurrent cancer or a drugresistant cancer, especially including a drug resistant cancer.Separately, metastatic cancer may be found in virtually all tissues of acancer patient in late stages of the disease, typically metastaticcancer is found in lymph system/nodes (lymphoma), in bones, in lungs, inbladder tissue, in kidney tissue, liver tissue and in virtually anytissue, including brain (brain cancer/tumor). Thus, the presentdisclosure is generally applicable and may be used to treat any cancerin any tissue, regardless of etiology.

The term “tumor” is used to describe a malignant or benign growth ortumefacent.

The term “autoimmune disease” refers to a disease or illness that occurswhen the body tissues are attacked by its own immune system. The immunesystem is a complex organization within the body that is designednormally to “seek and destroy” invaders of the body, includinginfectious agents. In diseases which are described as autoimmunediseases, MIF levels are often elevated. The present disclosure seeks toinhibit or lower elevated MIF levels in patients with autoimmune disease(as well as inflammatory diseases and conditions and cancer) and bydecreasing MIF levels, ameliorate many of the symptoms and secondaryeffects of these disease states and conditions. Examples of autoimmunediseases which often exhibit high expressed levels of MIF including, forexample, systemic lupus erythematosus, Sjogren syndrome, Hashimotothyroiditis, rheumatoid arthritis, juvenile (type 1) diabetes,polymyositis, scleroderma, Addison's disease, vtiligo, perniciousanemia, glomerulonephritis, and pulmonary fibrosis, among numerousothers.

A more complete list of autoimmune diseases which may be treated bycompounds and pharmaceutical compositions according to the presentdisclosure includes Addison's Disease, Autoimmune polyendodrine syndrome(APS) types 1, 2 and 3, autoimmune pancreatitis (AIP), diabetes mellitustype 1, autoimmune thyroiditis, Ord's thyroiditis, Grave's disease,autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren'ssyndrome, autoimmune enteropathy, coeliac disease, Crohns' disease,microscopic colitis, ulcerative colitis, autophospholipid syndrome(APlS), aplastic anemia, autoimmune hemolytica anemia, autoimmunelymphoproliferative syndrome, autoimmune neutropenia, autoimmunethrombocytopenic purpura, cold agglutinin disease, essential mixedcryoglulinemia, Evans sndrome, pernicious anemia, pure red cell aplasia,thrombocytopenia, adiposis dolorosa, adult-onset Still's disease,anklyosing spondylitis, CREST syndrome, drug-induced lupus,enthesitis-related arthritis, esosiniphilic fasciitis, Felty syndrome,AgG4-related disease, juvenile arthritis, Lyme disease (chronic), mixedconnective tissue dease (MCTD), palindromic rheurmatism, Parry Rombergsyndrome, Parsonage-Turner syndrome, psoriatic arthritis, reactivearthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumaticfever, rheumatoid arthritis, sarcoidosis, Schnitzler syndrome, systemiclupus erythematosus, undifferentiated connective tissue disease (UCTD),dematomyositis, fibromyalgia, myositis, inclusion body myositis,myasthenia gravis, neuromyotonia, paraneoplastic cerebellardegeneration, polymysositis, acute disseminated encephalomyelitis(ADEM), acute motor axonic neuropathy, anti-NMDA receptor encephalitis,Balo concentric sclerosis, Bickerstaff s encephalitis, chronicinflamatory demyelinating polyneuropathy, Guillain-Barre syndome,Hashimoto's encephalopathy, idiopathic inflammatory demyelinatingdiseases, Lambert-Eaton myasthenic syndrome, mutiple sclerosis, patternII, Oshtoran Syndrome, Pendiatric Autoimmune Neuropsychiatric DisorderAssociated with Streptococcus (PANDAS), progressive inflammatoryneuropathy, restless leg syndrome, stiff person syndrome, Syndenhamchorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis,Cogan syndrome, Graves ophthalmopathy, intermediate uveitis, ligneousconjunctivitis, Mooren's ulcer, neuromyelitis optica, opsoclonusmyoclonus syndrome, optic neuritis, scleritis, Susac's syndrome,sympathetic ophthalmia, Tolosa-Hunt syndrome, autoimmune inner eardisease (AIED), Méniére's disease, Behçet's disease, Eosiniphilicgranulomatosis with polyangiitis (EGPA), giant cell arteritis,granulomatosis with polyangiitis (GPA), IgA vasculitis (IgAV),Kawasaki's disease, leukocytoclastic vasculitis, lupus vasculitis,rheumatoid vasculitis, microscopic polyangiitis (MPA), polyarteritisnodosa (PAN), polymyalgia rheumatica, urticarial vasculitis, vasculitis,primary immune deficiency, chronic fatigue syndrome, complex regionalpain syndrome, eosiniphilic esopagitis, gastritis, interstitial lungdisease, POEMS syndrome, Raynaud's syndrome, primary immunodeficiencyand pyoderma gangrenosum, among others.

The term “inflammatory disease” is used to describe a disease or illnesswith acute, but more often chronic inflammation as a principalmanifestation of the disease or illness. Inflammatory diseases includediseases of neurodegeneration (including, for example, Alzheimer'sdisease, Parkinson's disease, Huntington's disease; other ataxias),diseases of compromised immune response causing inflammation (e.g.,dysregulation of T cell maturation, B cell and T cell homeostasis,counters damaging inflammation), chronic inflammatory diseasesincluding, for example, inflammatory bowel disease, including Crohn'sdisease, rheumatoid arthritis, lupus, multiple sclerosis, chronicobstructive pulmony disease/COPD, pulmonary fibrosis, cystic fibrosis,Sjogren's disease; hyperglycemic disorders, diabetes (I and II),affecting lipid metabolism islet function and/or structure, pancreaticβ-cell death and related hyperglycemic disorders, including severeinsulin resistance, hyperinsulinemia, insulin-resistant diabetes (e.g.Mendenhall's Syndrome, Werner Syndrome, leprechaunism, and lipoatrophicdiabetes) and dyslipidemia (e.g. hyperlipidemia as expressed by obesesubjects, elevated low-density lipoprotein (LDL), depressed high-densitylipoprotein (HDL), elevated triglycerides and metabolic syndrome, liverdisease, renal disease (apoptosis in plaques, glomerular disease),cardiovascular disease (especially including infarction, ischemia,stroke, pressure overload and complications during reperfusion), muscledegeneration and atrophy, low grade inflammation, gout, silicosis,atherosclerosis and associated conditions such as cardiac andneurological (both central and peripheral) manifestations includingstroke, age-associated dementia and sporadic form of Alzheimer'sdisease, and psychiatric conditions including depression), stroke andspinal cord injury, arteriosclerosis, among others. In these diseases,elevated MIF is very often observed, making these disease states and/orconditions response to therapy using compounds and/or pharmaceuticalcompositions according to the present disclosure. It is noted that thereis some overlap between certain autoimmune diseases and inflammatorydiseases as described herein.

The term “linker”, refers to a chemical entity including a complexlinker connecting a macrophage migration inhibitory factor bindingmoiety (MIFBM) to the asialoglycoprotein receptor binding moiety(ASGPRBM), optionally through at least one (such as one or two)connector moiety [CON] through covalent bonds in compounds according tothe present disclosure. The linker between the two active portions ofthe molecule, that is the MIFBM and the ASGPRBM ranges from about 5 Å toabout 50 Å or more in length, about 6 Å to about 45 Å in length, about 7Å to about 40 Å in length, about 8 Å to about 35 Å in length, about 9 Åto about 30 Å in length, about 10 Å to about 25 Å in length, about 7 Åto about 20 Å in length, about 5 Å to about 16 Å in length, about 5 Å toabout 15 Å in length, about 6 Å to about 14 Å in length, about 10 Å toabout 20 Å in length, about 11 Å to about 25 Å in length, etc. Linkerswhich are based upon ethylene glycol units and are between 2 and 15glycol units, 1 and 8 glycol units, 1, 2, 3, 4, 5, and 6 glycol units inlength may be used, although the length of certain linkers may be fargreater. By having a linker with a length as otherwise disclosed herein,the MIFBM group and the ASGPRBM group may be situated to advantageouslytake advantage of the biological activity of compounds according to thepresent disclosure which bind to asialoglycoprotein receptors onhepatocytes resulting in the selective and targeted degradation of MIFcirculating proteins within the lysosomal degradation mechanism or otherdegradation mechanism of the hepatocytes. The selection of a linkercomponent is based on its documented properties of biocompatibility,solubility in aqueous and organic media, and lowimmunogenicity/antigenicity.

Although numerous linkers may be used as otherwise described herein, alinker based upon polyethyleneglycol (PEG) linkages, polypropyleneglycol linkages, or polyethyleneglycol-co-polypropylene oligomers (up toabout 100 units, about 1 to 100, about 1 to 75, about 1 to 60, about 1to 50, about 1 to 35, about 1 to 25, about 1 to 20, about 1 to 15, 2 to10, about 4 to 12, about 1 to 8, 1 to 3, 1 to 4, 2 to 6, 1 to 5, etc.)may be favored as a linker because of the chemical and biologicalcharacteristics of these molecules. Polyethylene (PEG) linkages ofbetween 2 and 15 ethylene glycol units are sometimes used. Whendescribing linkers according to the present disclosure, includingpolyethylene glycol linkers or other linkers, one or more additionalgroups (e.g., methylene groups, amide groups, keto groups, amine groups,etc.) may be covalently attached at either end of the linker group toattach to a ASGPRBM group, a [CON] group, another linker group or a CPBMgroup.

Alternative linkers may include, for example, polyamino acid linkers ofup to 100 amino acids (of any type, such as D- or L-amino acids, such asnaturally occurring L-amino acids) in length (about 1 to 75, about 1 to60, about 1 to 50, about 1 to 45, about 1 to 35, about 1 to 25, about 1to 20, about 1 to 15, 2 to 10, about 4 to 12, about 5 to 10, about 4 to6, about 1 to 8, about 1 to 6, about 1 to 5, about 1 to 4, about 1 to 3,etc. in length), optionally including one or more connecting groups(such as 1 or 2 connecting groups at one or both ends of the polyaminoacid linker).

Exemplary linkers include those according to the chemical structures:

or a polypropylene glycol or polypropylene-co-polyethylene glycol linkerhaving between 1 and 100 alkylene glycol units, such as about 1 to 75,about 1 to 60, about 1 to 50, about 1 to 45, about 1 to 35, about 1 to25, about 1 to 20, about 1 to 15, 2 to 10, about 4 to 12, about 5 to 10,about 4 to 6, about 1 to 8, about 1 to 6, about 1 to 5, about 1 to 4,about 1 to 3;

where R_(a) is H, C₁-C₃ alkyl or alkanol or forms a cyclic ring with R³(proline) and R³ is a side chain derived from a D- or L amino acid (suchas a naturally occurring L-amino acid), such as selected from the groupconsisting of alanine (methyl), arginine (propyleneguanidine),asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid),cysteine (thiol, reduced or oxidized di-thiol), glutamine(ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H),histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine(2-methylpropane), lysine (butyleneamine), methionine(ethylmethylthioether), phenylalanine (benzyl), proline hydroxyproline(R³ forms a cyclic ring with R_(a) and the adjacent nitrogen group toform a pyrrolidine or hydroxypyrrolidine group), serine (methanol),threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole),tyrosine (methylene phenol) or valine (isopropyl);

m (within the context of this use) is an integer ranging from 1 to 100,such as from 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to35, 3 to 30, 1 to 5, 1 to 2, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5.

Other exemplary linkers include a polyethylene glycol linker containingfrom 1 to 1 to 100, such as to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or5 ethylene glycol units, to which is bonded a lysine group or otheramino acid moiety at one or both ends of the linker (which can consistof between 1 and 10 amino acids which can bind the MIFBM and/or theASGPRBM group. Still other linkers comprise amino acid residues (D or L)which are bonded to MIFBM and/or ASGPRBM moieties as otherwise describedherein. In another embodiment, as otherwise described herein, the aminoacid has anywhere from 1-15 methylene groups separating the amino groupfrom the acid (acyl) group in providing a linker to the MIFBM and/or theASGPRBM group, wherein the linker contains from 1 to 100, 1 to 75, 1 to60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5 amino acid groups linked togetherthrough peptide linkages to form the linker. This linker is representedby the chemical structure:

where R_(am) is H or a C₁-C₃ alkyl optionally substituted with one ortwo hydroxyl groups;

na is an integer ranging from 1 to 15, such as 1-12, 1-10, 1-8, 1, 2, 3,4, 5, 6, 7, 8, 9, 10 or 11;

m is an integer ranging from 1 to 100, such as 1 to 75, 1 to 60, 1 to55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 12, 1 to10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 51 to 50, 1 to 45, 1 to 40, 2 to 35, 3to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5.

or another linker is according to the chemical formula:

where Z and Z′ are each independently a bond, —(CH₂)_(i)—O,—(CH₂)_(i)—S, —(CH₂)_(i)—N—R,

wherein said —(CH₂)_(i) group, if present in Z or Z′, is bonded to aconnector (CON), MIFBM or ASGPRBM;

each R is H, or a C₁-C₃ alkyl or alkanol group;

each R² is independently H or a C₁-C₃ alkyl group;

each Y is independently a bond, O, S or N—R;

each i is independently an integer ranging from 0 to 100, such as 0 to75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to15, 1 to 10, 1 to 8, 1 to 6, 0, 1, 2, 3, 4 or 5;

D is

or

a bond, with the proviso that Z, Z′ and D are not each simultaneouslybonds;

j is an integer ranging from 1 to 100, such as 1 to 75, 1 to 60, 1 to55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 5, 1 to 10, 1 to8, 1 to 6, 1, 2, 3, 4 or 5;

m′ is an integer ranging from 1 to 100, such as 1 to 75, 1 to 60, 1 to55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 5, 1 to 10, 1 to8, 1 to 6, 1, 2, 3, 4 or 5;

n is an integer ranging from 1 to 100, such as 1 to 75, 1 to 60, 1 to55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 5, 1 to 10, 1 to8, 1 to 6, 1, 2, 3, 4 or 5;

X¹ is O, S or N—R; and

R is H, or a C₁-C₃ alkyl or alkanol group, or a pharmaceutical saltthereof.

Other linkers which are included herein include linkers according to thechemical structure:

where each n and n′ is independently an integer ranging from 1 to 25,such as 1 to 15, 1 to 12, 2 to 11, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to4 and 2 to 3 or 1, 2, 3, 4, 5, 6, 7, or 8; and

each n″ is independently an integer ranging from 0 to 8, such as 1 to 7,or 1, 2, 3, 4, 5 or 6.

Linkers also can comprise two or more linker segments (based upon thelinkers described above) which are attached directly to each other orthrough [CON] groups forming a complex linker. Certain linkers whichinclude a [CON] group (especially a diamide [CON] group as otherwisedescribed herein) connecting a first and second (PEG) linker groupinclude the following structures:

where each n and n′ is independently an integer ranging from 1 to 25,such as 1 to 15, 1 to 12, 2 to 11, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to4 and 2 to 3 or 1, 2, 3, 4, 5, 6, 7, or 8; and

each n″ is independently an integer ranging from 0 to 8, such as 1 to 7,or 1, 2, 3, 4, 5 or 6. Noted is that each of these linkers may alsocontain alkylene groups containing from 1 to 4 methylene groups at thedistal ends of each linker group in order to facilitate connection ofthe linker group.

Other linkers which include a connector group [CON] include groups whichare represented by the chemical formula PEG-[CON]-PEG

wherein each PEG is independently a polyethylene glycol group containingfrom 1-12 ethylene glycol residues and [CON] is a connector group asotherwise set forth herein, such as a triazole group

The term “connector”, symbolized in the generic formulas by “CON” or[CON], is used to describe a chemical moiety which is optionallyincluded in bifunctional compounds according to the present disclosurewhich forms from the reaction product of an activated linker with aMIFBM moiety (which also is sometimes activated for covalently bondingthe linker with the moiety) or a ASGPRBM group with an activated linker.The connector group is often the resulting moiety which forms from thefacile condensation of two or more separate chemical fragments whichcontain reactive groups which can provide connector groups as otherwisedescribed to produce bifunctional or multifunctional compounds accordingto the present disclosure. It is noted that a connector may bedistinguishable from a linker in that the connector is the result of aspecific chemistry which is used to provide bifunctional compoundsaccording to the present disclosure wherein the reaction product ofthese groups results in an identifiable connector group or part of aconnector group which is distinguishable from the linker group, althoughin certain instances, the connector group is incorporated into andintegral with the linker group as otherwise described herein. It isnoted also that a connector group may be linked to a number of linkersto provide multifunctionality (i.e., more than one CPBM moiety and/ormore than one ASGPRBM/FCRNBM moiety) within the same molecule. It isnoted that there may be some overlap between the description of theconnector group and the linker group such that the connector group isactually incorporated or forms part of the linker, especially withrespect to more common connector groups such as amide groups, oxygen(ether), sulfur (thioether) or amine linkages, urea or carbonate—OC(O)O— groups or as otherwise described herein. It is further notedthat a connector (or linker) may be connected to MIFBM, ASGPRBM or alinker at positions which are represented as being linked to anothergroup using the symbol

Where two or more such groups are present in a linker or connector, anyof an ASGPRBM, a linker or a MIFBM may be bonded to such a group. Wherethat symbol is not used, the linker may be at one or more positions of amoiety.

Common connector groups which are used in the present disclosure includethe following chemical groups:

and the like

where R^(CON1) and R^(CON2) are each independently H, methyl or a bond(for attachment to another moiety); or

a diamide group according to the structure:

where X² is CH₂, O, S, NR⁴, C(O), S(O), S(O)₂, —S(O)₂O, —OS(O)₂, orOS(O)₂O;

X³ is O, S, NR⁴;

R⁴ is H, a C₁-C₃ alkyl or alkanol group, or a —C(O)(C₁-C₃) group;

R₁ is H or a C₁-C₃ alkyl group; and

n″ is independently an integer ranging from 0 to 8, such as 1 to 7, or1, 2, 3, 4, 5 or 6;

or the connector group [CON] is a group according to the chemicalstructure:

where R^(1CON), R^(2CON) and R^(3CON) are each independently H,—(CH₂)_(MC1), —(CH₂)_(MC1a)C(O)_(XA)(NR⁴)_(XA)—(CH₂)_(MC1a),—(CH₂)_(MC1a)(NR⁴)_(XA)C(O)_(XA)—(CH₂)_(MC1a) or—(CH₂)_(MC1a)O—(CH₂)_(MC1)—C(O)NR⁴—, with the proviso that R^(1CON),R^(2CON) and R^(3CON) are not simultaneously H;

each MC1 is independently an integer ranging from 1 to 4, such as 1 or2;

each MC1a is independently an integer ranging from 0 to 4, such as 0, 1or 2; and

R⁴ is H, a C₁-C₃ alkyl or alkanol group, or a —C(O)(C₁-C₃) group.

The triazole group, indicated above, is an exemplary connector group. Anadditional exemplary connector group is

which is linked to at least one MIFBM and/or at least one ASPRGBM (suchas 3 ASPRGBM moieties). This connector group may be used to form GN₃.

It is noted that each connector may be extended with one or moremethylene groups to facilitate connection to a linker group, another CONgroup, a MIFBM group or a ASGPRBM. It is noted that in certaininstances, within context the diamide group may also functionindependently as a linker group.

Additional Galactose- and Talose-Based ASGPR Binding Moieties

In certain embodiments, the present disclosure is directed to compoundswhich are useful for removing circulating proteins which are associatedwith a disease state or condition in a patient or subject according tothe general chemical structure of Formula II:

The term “Extracellular Protein Targeting Ligand” as used herein isinterchangeably used with the term CPBM (cellular protein bindingmoiety). The term “ASGPR Ligand” as used herein is interchangeably usedwith an asialoglycoprotein receptor (ASGPR) binding moiety as definedherein.

In the compound of Formula II, each [CON] is an optional connectorchemical moiety which, when present, connects directly to [CPBM] or to[CRBM] or connects the [LINKER-2] to [CPBM] or to [CRBM].

In the compound of Formula II:

[LINKER-2] is a chemical moiety having a valency from 1 to 15 whichcovalently attaches to one or more [CRBM] and/or [CPBM] group,optionally through a [CON], including a [MULTICON] group, wherein said[LINKER-2] optionally itself contains one or more [CON] or [MULTICON]group(s);

k′ is an integer from 1 to 15;

j′ is an integer from 1 to 15;

h and h′ are each independently an integer from 0 to 15;

i_(L) is an integer from 0 to 15;

with the proviso that at least one of h, h′ and i_(L) is at least 1, ora pharmaceutically acceptable salt, stereoisomer, solvate or polymorphthereof.

A [MULTICON] group can connect one or more of a [CRBM] or [CPBM] to oneor more of a [LINKER-2]. In various embodiments, [LINKER-2] has avalency of 1 to 10. In various embodiments, [LINKER-2] has a valency of1 to 5. In various embodiments, [LINKER-2] has a valency of 1, 2 or 3.In various embodiments, in the compound of Formula II, the [LINKER-2]includes one or more of Linker^(A), Linker^(B), Linker^(C), Linker^(D),and/or combinations thereof as defined herein.

In the compound of Formula II, xx is independently selected from 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, and 25.

In the compound of Formula II, yy is independently selected from 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, and 25.

In the compound of Formula II, zz is independently selected from 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, and 25.

In the compound of Formula II, X¹ is 1 to 5 contiguous atomsindependently selected from O, S, N(R^(b)), and C(R⁴)(R⁴), wherein if X¹is 1 atom then X¹ is O, S, N(R⁶), or C(R⁴)(R⁴), if X¹ is 2 atoms then nomore than 1 atom of X¹ is O, S, or N(R⁶), if X¹ is 3, 4, or 5 atoms thenno more than 2 atoms of X¹ are O, S, or N(R₆);

R³ at each occurrence is independently selected from hydrogen, alkyl,heteroalkyl, haloalkyl (including —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, —CH₂CH₂F,and —CF₂CF₃), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and,heteroaryl, heterocycle, —OR⁸, and —NR⁸R⁹;

R⁴ is independently selected at each occurrence from hydrogen,heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocycle, —OR⁶, —NR⁶R⁷,

R⁶ and R⁷ are independently selected at each occurrence from hydrogen,heteroalkyl, alkyl, arylalkyl, heteroaryl alkyl, alkenyl, alkynyl, and,haloalkyl, heteroaryl, heterocycle, -alkyl-OR⁸, -alkyl-NR⁸R⁹, C(O)R³,S(O)R³, C(S)R³, and S(O)₂R³;

R⁸ and R⁹ are independently selected at each occurrence from hydrogen,heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocycle.

A. Galactose-Based ASGPR-Binding Cellular Receptor Binding Moieties ofFormula II

In certain embodiments, the compound of Formula II is selected from:

In certain embodiments, the compound of Formula II has one of thefollowing structures:

In various embodiments, the ASGPR ligand is linked at either the C¹ orC⁵ (R¹ or R⁵) position to form a degrading compound. In variousembodiments, the ASGPR ligand is linked at C⁶ position to form adegrading compound. For example, when the ASGPR ligand is

then non-limiting examples of ASGPR binding compounds of Formula IIinclude:

or the bi- or tri-substituted versions thereof or pharmaceuticallyacceptable salts thereof, where the bi- or tri-substitution refers tothe number additional galactose derivatives attached to a linker moiety.

In any of the embodiments herein where an ASGPR ligand is drawn for usein a degrader the ASGPR ligand is typically linked through to theExtracellular Protein Targeting Ligand in the C⁵ position (e.g., whichcan refer to the adjacent C⁶ carbon hydroxyl or other functional moietythat can be used for linking purposes). When the linker andExtracellular Protein Targeting Ligand is connected through the C¹position, then that carbon is appropriately functionalized for linking,for example with a hydroxyl, amino, allyl, alkyne or hydroxyl-allylgroup.

In various embodiments, the ASGPR ligand is not linked in the C³ or C⁴position, because these positions chelate with the calcium for ASGPRbinding in the liver. In certain embodiments, an ASGPR ligand useful forincorporation into a compound of Formula II is selected from:

In certain embodiments, the compound of Formula II is selected from.

B. Talose-Based ASGPR-Binding Cellular Receptor Binding Moieties ofFormula II

In certain embodiments, the compound of Formula II is selected from.

In certain embodiments, the compound of Formula II is an ExtracellularProtein degrading compound in which the ASGPR ligand is a ligand asdescribed herein

In certain embodiments, in the compound of Formula II, the ASGPR ligandis linked at either the C1 or C5 (R¹ or R⁵) position to form a degradingcompound. In certain embodiments, in the compound of Formula II, theASGPR ligand is linked at C6. In various embodiments, when the ASGPRligand is

then non-limiting examples of ASGPR binding compounds of Formula IIinclude:

or the bi- or tri-substituted versions thereof or pharmaceuticallyacceptable salts thereof, where the bi- or tri-substitution refers tothe number additional galactose derivatives attached to a linker moiety.In certain embodiments the compound of Formula II is selected from:

wherein in certain embodiments R² is selected from —NR⁶COR³,—NR⁶-(5-membered heteroaryl), and —NR⁶-(6-membered heteroaryl), each ofwhich R² groups is optionally substituted with 1, 2, 3, or 4independent, substituents as described herein, for example 1, 2, 3, or 4substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

In certain embodiments, the compound of Formula II is selected from:

wherein in certain embodiments R² is selected from —NR⁶COR³,—NR⁶-(5-membered heteroaryl), and —NR⁶-(6-membered heteroaryl), each ofwhich R² groups is optionally substituted with 1, 2, 3, or 4independent, substituents as described herein, for example 1, 2, 3, or 4substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

In certain embodiments, the compound of Formula II is selected from.

wherein in certain embodiments R² is selected from —NR⁶COR³,—NR⁶-(5-membered heteroaryl), and —NR⁶-(6-membered heteroaryl), each ofwhich R² groups is optionally substituted with 1, 2, 3, or 4independent, substituents as described herein, for example 1, 2, 3, or 4substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

In certain embodiments, the compound of Formula II is selected from:

wherein in certain embodiments R² is selected from —NR⁶COR³,—NR⁶-(5-membered heteroaryl), and —NR-(6-membered heteroaryl), each ofwhich R² groups is optionally substituted with 1, 2, 3, or 4independent, substituents as described herein, for example 1, 2, 3, or 4substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

In certain embodiments, the compound of Formula II is selected from:

wherein in certain embodiments R² is selected from —NR⁶COR³,—NR⁶-(5-membered heteroaryl), and —NR⁶-(6-membered heteroaryl), each ofwhich R² groups is optionally substituted with 1, 2, 3, or 4independent, substituents as described herein, for example 1, 2, 3, or 4substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

In certain embodiments, the compound of Formula II is selected from.

wherein in certain embodiments R² is selected from —NR⁶COR³,—NR⁶-(5-membered heteroaryl), and —NR⁶-(6-membered heteroaryl), each ofwhich R² groups is optionally substituted with 1, 2, 3, or 4independent, substituents as described herein, for example 1, 2, 3, or 4substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

In certain embodiments, the compound of Formula II is selected from.

wherein in certain embodiments R² is selected from —NR⁶COR³,—N⁶-(5-membered heteroaryl), and —NR⁶-(6-membered heteroaryl), each ofwhich R² groups is optionally substituted with 1, 2, 3, or 4independent, substituents as described herein, for example 1, 2, 3, or 4substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

In certain embodiments, the compound of Formula II is selected from:

wherein in certain embodiments R² is selected from —NR⁶COR¹⁰,—NR⁶-(5-membered heteroaryl), and —NR⁶-(6-membered heteroaryl), each ofwhich R² groups is optionally substituted with 1, 2, 3, or 4independent, substituents as described herein, for example 1, 2, 3, or 4substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

In certain embodiments, the compound of Formula II is selected from.

wherein in certain embodiments R² is selected from —NR^(b)COR¹⁰,—NR⁶-(5-membered heteroaryl), and —NR⁶-(6-membered heteroaryl), each ofwhich R² groups is optionally substituted with 1, 2, 3, or 4independent, substituents as described herein, for example 1, 2, 3, or 4substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

In certain embodiments, the compound of Formula II is selected from:

wherein in certain embodiments R² is selected from —NR⁶COR¹⁰,—NR⁶-(5-membered heteroaryl), and —NR⁶-(6-membered heteroaryl), each ofwhich R² groups is optionally substituted with 1, 2, 3, or 4independent, substituents as described herein, for example 1, 2, 3, or 4substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

In certain embodiments, the compound of Formula II is selected from:

wherein in certain embodiments R² is selected from —NR⁶COR¹⁰,—NR⁶-(5-membered heteroaryl), and —NR⁶-(6-membered heteroaryl), each ofwhich R² groups is optionally substituted with 1, 2, 3, or 4independent, substituents as described herein, for example 1, 2, 3, or 4substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

In certain embodiments, the compound of Formula II is selected from:

wherein in certain embodiments R² is selected from —NR⁶COR¹⁰,—NR⁶-(5-membered heteroaryl), and —NR⁶-(6-membered heteroaryl), each ofwhich R² groups is optionally substituted with 1, 2, 3, or 4independent, substituents as described herein, for example 1, 2, 3, or 4substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

In certain embodiments, the compound of Formula II is selected from:

wherein in certain embodiments R² is selected from —NR⁶COR¹⁰,—NR⁶-(5-membered heteroaryl), and —NR⁶-(6-membered heteroaryl), each ofwhich R² groups is optionally substituted with 1, 2, 3, or 4independent, substituents as described herein, for example 1, 2, 3, or 4substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

In certain embodiments, the compound of Formula II is selected from:

wherein in certain embodiments R² is selected from —NR⁶COR¹⁰,—NR⁶-(5-membered heteroaryl), and —NR⁶-(6-membered heteroaryl), each ofwhich R² groups is optionally substituted with 1, 2, 3, or 4independent, substituents as described herein, for example 1, 2, 3, or 4substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

In certain embodiments, the compound of Formula II is selected from.

In certain embodiments an ASGPR ligand useful for incorporation into acompound of Formula II is selected from:

C. The ASGPR LigandBinding Moiety in Compounds of Formula II

In certain embodiments, in the compound of Formula II, R¹ is hydrogen.

In certain embodiments, in the compound of Formula II, R¹ is

In certain embodiments, in the compound of Formula II, R¹ is

In certain embodiments, in the compound of Formula II, R₁ is

In certain embodiments, in the compound of Formula II, R¹ is

In certain embodiments, in the compound of Formula II, R¹ is

In certain embodiments, in the compound of Formula II, R¹ is

In certain embodiments, in the compound of Formula II, R¹ isC₀-C₆alkyl-cyano optionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R¹ is alkyloptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R¹ is alkenyloptionally substituted with 1, 2, 3, or 4 substituents. In certainembodiments, in the compound of Formula II, R¹ is alkynyl optionallysubstituted with 1, 2, 3, or 4 substituents. In certain embodiments, inthe compound of Formula II, R¹ is haloalkyl optionally substituted with1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R¹ is F.

In certain embodiments, in the compound of Formula II, R¹ is Cl.

In certain embodiments, in the compound of Formula II, R¹ is Br.

In certain embodiments, in the compound of Formula II, R¹ is aryloptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R¹ is arylalkyloptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R¹ is heteroaryloptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R¹ is heteroarylalkyl optionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R¹ is heterocycleoptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R¹ isheterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R¹ is haloalkoxyoptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R¹ is —O-alkenyl,—O-alkynyl, C₀-C₆alkyl-OR⁶, C₀-C₆alkyl-SR⁶, C₀-C₆alkyl-NR⁶R⁷,C₀-C₆alkyl-C(O)R³, C₀-C₆alkyl-S(O)R³, C₀-C₆alkyl-C(S)R³,C₀-C₆alkyl-S(O)₂R³, C₀-C₆alkyl-N(R⁸)—C(O)R³, C₀-C₆alkyl-N(R⁸)—S(O)R³,C₀-C₆alkyl-N(R⁸)—C(S)R³, C₀-C₆alkyl-N(R⁸)—S(O)₂R³ C₀-C₆alkyl-O—C(O)R³,C₀-C₆alkyl-O—S(O)R³, C₀-C₆alkyl-O—C(S)R³, —N═S(O)(R³)₂, C₀-C₆alkylN₃, orC₀-C₆alkyl-O—S(O)₂R³, each of which is optionally substituted with 1, 2,3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is aryloptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is heterocycleoptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is heteroarylcontaining 1 or 2 heteroatoms independently selected from N, O, and Soptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is heterocycleoptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is—NR⁸—S(O)—R³ optionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is—NR⁸—C(S)—R³ optionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is—NR⁸—S(O)(NR⁶)—R³ optionally substituted with 1, 2, 3, or 4substituents.

In certain embodiments, in the compound of Formula II, R² is—N═S(O)(R³)₂ optionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is—NR⁸C(O)NR⁹S(O)₂R³ optionally substituted with 1, 2, 3, or 4substituents.

In certain embodiments, in the compound of Formula II, R² is—NR⁸—S(O)₂—R¹⁰ optionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is—NR⁸—C(NR⁶)—R³ optionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is hydrogen.

In certain embodiments, in the compound of Formula II, R² is R¹⁰,

In certain embodiments, in the compound of Formula II, R² isalkyl-C(O)—R³.

In certain embodiments, in the compound of Formula II, R² is —C(O)—R³.

In certain embodiments, in the compound of Formula II, R² is alkyl.

In certain embodiments, in the compound of Formula II, R² is haloalkyl.

In certain embodiments, in the compound of Formula II, R² is —OC(O)R³.

In certain embodiments, in the compound of Formula II, R² is—NR⁸—C(O)R¹⁰.

In certain embodiments, in the compound of Formula II, R² is alkenyloptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is allyloptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is alkynyloptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is—NR⁶-alkenyl optionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is —O-alkenyloptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is —NR-alkynyloptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is—NR⁶-heteroaryl optionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is —NR⁶-aryloptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is—O-heteroaryl optionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is —O-aryloptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is —O-alkynyloptionally substituted with 1, 2, 3, or 4 substituents.

In certain embodiments, in the compound of Formula II, R² is selectedfrom and

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

wherein R is an optional substituent as defined herein.

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments in the compound of Formula II, R^(2A) is selectedfrom

wherein R is an optional substituent as defined herein.

In certain embodiments, in the compound of Formula II, R^(2A) isselected from

In certain embodiments, in the compound of Formula II R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments in the compound of Formula II, R² is selectedfrom

In certain embodiments in the compound of Formula II, R² is selectedfrom

In certain embodiments in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments in the compound of Formula II R² is selected from

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² or R^(2A) isselected from

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is selectedfrom

In certain embodiments, in the compound of Formula II, R² is aspirocyclic heterocycle, for example, and without limitation,

In certain embodiments, in the compound of Formula II, R² is a siliconcontaining heterocycle, for example, and without limitation,

In certain embodiments, in the compound of Formula II, R² is substitutedwith SFs, for example, and without limitation,

In certain embodiments, in the compound of Formula II, R² is substitutedwith a sulfoxime, for example, and without limitation,

In certain embodiments, in the compound of Formula II, R¹⁰ is selectedfrom bicyclic heterocycle.

In certain embodiments, in the compound of Formula II, R¹⁰ is selectedfrom spirocyclic heterocycle.

In certain embodiments, in the compound of Formula II, R¹⁰ is selectedfrom —NR⁶— heterocycle.

In certain embodiments, in the compound of Formula II, R¹⁰ is selectedfrom

In certain embodiments, in the compound of Formula II, R¹⁰ is selectedfrom

In certain embodiments, in the compound of Formula II, R¹⁰ is selectedfrom

In certain embodiments, in the compound of Formula II, R¹⁰ is selectedfrom

In certain embodiments, in the compound of Formula II, Cycle is selectedfrom

In certain embodiments, in the compound of Formula II, R³⁰ is selectedfrom:

In certain embodiments, in the compound of Formula II, R²⁰⁰ is

In certain embodiments, in the compound of Formula II, R²⁰⁰ is

In certain embodiments, in the compound of Formula II, R²⁰⁰ is

In certain embodiments, in the compound of Formula II, R²⁰⁰ is

In certain embodiments, in the compound of Formula II, R²⁰⁰ is

In certain embodiments, in the compound of Formula II, R²⁰⁰ is

In certain embodiments, in the compound of Formula II, R²⁰⁰ is

In certain embodiments, in the compound of Formula II, R²⁰⁰ is

In certain embodiments, in the compound of Formula II, R²⁰⁰ is

In certain embodiments, in the compound of Formula II, R²⁰⁰ is

In certain embodiments, in the compound of Formula II, R²⁰⁰ is

In certain embodiments, in the compound of Formula II, R²⁰⁰ is

Linkers

In non-limiting embodiments, in the compound of Formula II, Linker^(A)and Linker^(B) are independently selected from:

wherein:

R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, and R²⁰ are independentlyat each occurrence selected from the group consisting of a bond, alkyl,—C(O)—, —C(O)O—, —OC(O)—, —SO₂—, —S(O)—, —C(S)—, —C(O)NR⁶—, —NR⁶C(O)—,—O—, —S—, —NR⁶—, —C(R²¹R²¹)—, —P(O)(R³)O—, —P(O)(R³)—, a divalentresidue of a natural or unnatural amino acid, alkenyl, alkynyl,haloalkyl, alkoxy, and, heterocycle, heteroaryl,—CH₂CH₂—[O—(CH₂)₂]_(n)—O—, CH₂CH₂—[O—(CH₂)₂]_(n)—NR⁶—,—CH₂CH₂—[O—(CH₂)₂]_(n)—, —[—(CH₂)₂—O—]_(n)—, —[O—(CH₂)₂]_(n)—,—[O—CH(CH₃)C(O)]_(n)—, —[C(O)—CH(CH₃)—O]_(n)—,

—[O—CH₂C(O)]_(n)—, —[C(O)—CH₂—O]_(n)—, a divalent residue of a fattyacid, a divalent residue of an unsaturated or saturated mono- ordi-carboxylic acid; each of which is optionally substituted with 1, 2,3, or 4 substituents independently selected from R²¹;

n is independently selected at each instance from 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10;

R²¹ is independently at each occurrence selected from the groupconsisting of hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl,alkoxy, azide, amino, cyano, —NR⁶R⁷, —NR⁸SO₂R³, —NR⁸S(O)R³, haloalkyl,heteroalkyl, and, heteroaryl, and heterocycle;

and the remaining variables are as defined herein.

In certain embodiments, in the compound of Formula II, Linker^(A) isbond and Linker^(B) is

In certain embodiments, in the compound of Formula II, Linker^(B) isbond and Linker^(A) is

In certain embodiments in the compound of Formula II, a divalent residueof an amino acid is selected from

wherein the amino acid can be oriented in either direction and whereinthe amino acid can be in the L- or D-form or a mixture thereof.

In certain embodiments, in the compound of Formula II, a divalentresidue of a dicarboxylic acid is generated from a nucleophilic additionreaction.

Non-limiting embodiments of a divalent residue of a dicarboxylic acidgenerated from a nucleophilic addition reaction include:

In certain embodiments, in the compound of Formula II, a divalentresidue of a dicarboxylic acid is generated from a condensationreaction:

Non-limiting embodiments of a divalent residue of a dicarboxylic acidgenerated from a condensation include:

Non-limiting embodiments of a divalent residue of a saturateddicarboxylic acid include:

Non-limiting embodiments of a divalent residue of a saturateddicarboxylic acid include:

Non-limiting embodiments of a divalent residue of a saturatedmonocarboxylic acid is selected from butyric acid (—OC(O)(CH₂)₂CH₂—),caproic acid (—OC(O)(CH₂)₄CH₂—), caprylic acid (—OC(O)(CH₂)₅CH₂—),capric acid (—OC(O)(CH₂)₈CH₂—), lauric acid (—OC(O)(CH₂)₁₀CH₂—),myristic acid (—OC(O)(CH₂)₁₂CH₂—), pentadecanoic acid(—OC(O)(CH₂)₁₃CH₂—), palmitic acid (—OC(O)(CH₂)₁₄CH₂—), stearic acid(—OC(O)(CH₂)₁₆CH₂—), behenic acid (—OC(O)(CH₂)₂₀CH₂—), and lignocericacid (—OC(O)(CH₂)₂₂CH₂—);

Non-limiting embodiments of a divalent residue of a fatty acid includeresidues selected from linoleic acid, palmitoleic acid, vaccenic acid,paullinic acid, oleic acid, elaidic acid, gondoic acid, gadoleic acid,nervonic acid, myristoleic acid, and erucic acid:

Non-limiting embodiments of a divalent residue of a fatty acid isselected from linoleic acid (—C(O)(CH₂)₇(CH)₂CH₂(CH)₂(CH₂)₄CH₂—),docosahexaenoic acid

(—C(O)(CH₂)₂(CHCHCH₂)₆CH₂—), eicosapentaenoic acid(—C(O)(CH₂)₃(CHCHCH₂)₅CH₂—), alpha-linolenic acid(—C(O)(CH₂)₇(CHCHCH₂)₃CH₂—) stearidonic acid

(—C(O)(CH₂)₄(CHCHCH₂)₄CH₂—), y-linolenic acid(—C(O)(CH₂)₄(CHCHCH₂)₃(CH₂)₃CH₂—), arachidonic acid(—C(O)(CH₂)₃(CHCHCH₂)₄(CH₂)₄CH₂—), docosatetraenoic acid

(—C(O)(CH₂)₅(CHCHCH₂)₄(CH₂)₄CH₂—), palmitoleic acid(—C(O)(CH₂)₇CHCH(CH₂)₅CH₂—), vaccenic acid (—C(O)(CH₂)₉CHCH(CH₂)₅CH₂—),paullinic acid

(—C(O)(CH₂)₁₁CHCH(CH₂)₅CH₂—), oleic acid (—C(O)(CH₂)₇CHCH(CH₂)₇CH₂—),elaidic acid

(—C(O)(CH₂)₇CHCH(CH₂)₇CH₂—), gondoic acid (—C(O)(CH₂)₉CHCH(CH₂)₇CH₂—),gadoleic acid (—C(O)(CH₂)₇CHCH(CH₂)₉CH₂—), nervonic acid(—C(O)(CH₂)₁₃CHCH(CH₂)₃CH₂—), mead acid(—C(O)(CH₂)₃(CHCHCH₂)₃(CH₂)₆CH₂—), myristoleic acid(—C(O)(CH₂)₇CHCH(CH₂)₃CH₂—), and erucic acid(—C(O)(CH₂)₁₁CHCH(CH₂)₇CH₂—).

In certain embodiments, in the compound of Formula II, Linker^(C) isselected from.

wherein:

R²² is independently at each occurrence selected from the groupconsisting of alkyl, —C(O)N—, —NC(O)—, —N—, —C(R²¹)—, —P(O)O—, —P(O)—,—P(O)(NR⁶R⁷)N—, alkenyl, haloalkyl, aryl, heterocycle, and heteroaryl,each of which is optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

and the remaining variables are as defined herein.

In certain embodiments, in the compound of Formula II, Linker^(D) isselected from:

wherein:

R³² is independently at each occurrence selected from the groupconsisting of alkyl, N⁺X−, —C—, alkenyl, haloalkyl, aryl, heterocycle,and heteroaryl, each of which is optionally substituted with 1, 2, 3, or4 substituents independently selected from R²¹;

X− is an anionic group, for example Br− or C⁻; and

all other variables are as defined herein.

In certain embodiments, in the compound of Formula II, Linker^(A) isselected from:

wherein each heteroaryl, heterocycle, cycloalkyl, and aryl canoptionally be substituted with 1, 2, 3, or 4 of any combination ofhalogen, alkyl, haloalkyl, and, heteroaryl, heterocycle, or cycloalkyl,as allowed by valence.

In certain embodiments, in the compound of Formula II, Linker^(A) isselected from:

wherein each heteroaryl, heterocycle, cycloalkyl, and can optionally besubstituted with 1, 2, 3, or 4 of any combination of halogen, alkyl,haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl, as allowed byvalence.

In certain embodiments, in the compound of Formula II, Linker^(B) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(B),Linker^(C), or Linker^(D) is selected from:

wherein tt is independently selected from 1, 2, or 3 and ss is 3 minustt (3-tt).

In certain embodiments, in the compound of Formula II, Linker^(B),Linker^(C), or Linker^(D) is selected from:

wherein tt and ss are as defined herein.

In certain embodiments, in the compound of Formula II, Linker^(B),Linker^(C), or Linker^(D) is selected from:

wherein each heteroaryl, heterocycle, cycloalkyl, and aryl canoptionally be substituted with 1, 2, 3, or 4 of any combination ofhalogen, alkyl, haloalkyl, aryl, heteroaryl, heterocycle, or cycloalkyl,as allowed by valence; and tt and ss are as defined herein.

In certain embodiments, in the compound of Formula II, Linker^(B),Linker^(C), or Linker^(D) is selected from:

wherein each heteroaryl, heterocycle, cycloalkyl, and aryl canoptionally be substituted with 1, 2 3, or 4 of any combination ofhalogen, alkyl, haloalkyl, and, heteroaryl, heterocycle, or cycloalkyl,as allowed by valence: and tt and ss are as defined herein.

In certain embodiments, in the compound of Formula II, Linker^(B),Linker^(C), or Linker^(D) is selected from:

wherein each heteroaryl and aryl can optionally be substituted with 1,2, 3, or 4 of any combination of halogen, alkyl, haloalkyl, aryl,heteroaryl, heterocycle, or cycloalkyl, as allowed by valence; and ttand ss are as defined herein.

In certain embodiments, in the compound of Formula II, Linker^(A) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(A) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(A) isselected from:

In certain embodiments in the compound of Formula II Linker^(A) isselected from:

In certain embodiments in the compound of Formula II Linker^(B) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(B) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(B) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(B) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(C) isselected from.

In certain embodiments in the compound of Formula II Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(D) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(D) isselected from:

In certain embodiments, in the compound of Formula II, LinkerD isselected from.

In certain embodiments, in the compound of Formula II, Linker^(D) isselected from.

In certain embodiments, in the compound of Formula II, Linker^(D) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(D) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(D) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(A) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(A) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(A) isselected from:

In certain embodiments, the Linker^(A) is selected from:

wherein each is optionally substituted with 1, 2, 3, or 4 substituentssubstituent selected from R²¹.

In certain embodiments, in the compound of Formula II, Linker^(A) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(A) isselected from

In certain embodiments, in the compound of Formula II, the Linker^(A) isselected from

In certain embodiments, in the compound of Formula II, the Linker^(A) isselected from

In certain embodiments in the compound of Formula II, the Linker^(A) isselected from

In certain embodiments, in the compound of Formula II, the Linker^(A) isselected from

In certain embodiments, in the compound of Formula II, the Linker^(A) isselected from

In certain embodiments, in the compound of Formula II, the Linker^(A) isselected from

In certain embodiments, in the compound of Formula II, the Linker^(A) isselected from

In certain embodiments, in the compound of Formula II, the Linker^(A) isselected from

In certain embodiments, in the compound of Formula II, the Linker^(A) isselected from

In certain embodiments, in the compound of Formula II, the Linker^(A) isselected from

In certain embodiments in the compound of Formula II, the Linker^(A) isselected from

In certain embodiments, in the compound of Formula II, the Linker^(A) isselected from

In certain embodiments, in the compound of Formula II, the Linker^(A) isselected from

In certain embodiments, in the compound of Formula II, the Linker^(B) isselected from

In certain embodiments, in the compound of Formula II the Linker^(B) isselected from

In certain embodiments, in the compound of Formula II, the Linker^(B) isselected from

In certain embodiments, in the compound of Formula II, the Linker^(B) isselected from wherein each is optionally substituted with 1, 2, 3, or 4substituents substituent selected from R²¹.

In certain embodiments, in the compound of Formula II Linker^(B) isselected from.

In certain embodiments, in the compound of Formula II, the Linker^(B) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(B) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(B) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(B) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(B) isselected from:

In certain embodiments in the compound of Formula II the Linker^(B) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(B) isselected from:

In certain embodiments, in the compound of Formula II,Linker^(B)-Linker^(A) is selected from:

In certain embodiments, in the compound of Formula II,Linker^(B)-Linker^(A) is selected from:

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II the Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from.

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from: wherein each is optionally substituted with 1, 2, 3, or 4substituents substituent selected from R²¹.

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II, the Linker^(C) isselected from:

In certain embodiments, in the compound of Formula II,Linker^(C)-(Linker^(A))₂ is selected from:

In certain embodiments in the compound of Formula II,Linker^(C)-(Linker^(A))₂ is selected from:

In certain embodiments, in the compound of Formula II,Linker^(C)-(Linker^(A))₂ is selected from:

In certain embodiments, in the compound of Formula II,Linker^(C)-(Linker^(A))₂ is selected from:

In certain embodiments, in the compound of Formula II, Linker^(D) isselected from:

In certain embodiments, in the compound of Formula II, Linker^(D) isselected from:

wherein each is optionally substituted with 1, 2, 3, or 4 substituentsare selected from R²¹.

In certain embodiments, in the compound of Formula II,Linker^(B)-(Linker^(A)) is selected from

In certain embodiments, in the compound of Formula II,Linker^(C)-(Linker^(A)) is selected from

In certain embodiments, in the compound of Formula II,Linker^(D)-(Linker^(A)) is selected from

In various embodiments, R⁴ is independently selected at each occurrencefrom hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl,heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, —OR⁶,—NR⁶R⁷, C(O)R³, S(O)R³, C(S)R³, and S(O)₂R³.

In various embodiments, in the compound of Formula II, R⁵ isindependently selected from hydrogen, heteroalkyl,

C₀-C₆alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I,aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle,heterocycloalkyl, haloalkoxy, —O-alkenyl, —O-alkynyl, C₀-C₆alkyl-OR⁶,C₀-C₆alkyl-SR⁶, C₀-C₆alkyl-NR⁶R⁷, C₀-C₆alkyl-C(O)R³, C₀-C₆alkyl-S(O)R³,C₀-C₆alkyl-C(S)R³, C₀-C₆alkyl-S(O)₂R³, C₀-C₆alkyl-N(R⁸)—C(O)R³,C₀-C₆alkyl-N(R⁸)—S(O)R³, C₀-C₆alkyl-N(R⁸)—C(S)R³,C₀-C₆alkyl-N(R′)—S(O)₂R³ C₀-C₆alkyl-O—C(O)R³, C₀-C₆alkyl-O—S(O)R³,C₀-C₆alkyl-O—C(S)R³, —N═S(O)(R³)₂, C₀-C₆alkylN₃, andC₀-C₆alkyl-O—S(O)₂R³, each of which is optionally substituted with 1, 2,3, or 4 substituents.

In various embodiments, in the compound of Formula II, R⁶ and R⁷ areindependently selected at each occurrence from hydrogen, heteroalkyl,alkyl, arylalkyl, heteroaryl alkyl, alkenyl, alkynyl, and, haloalkyl,heteroaryl, heterocycle, -alkyl-OR⁸, -alkyl-NR⁸R⁹, C(O)R³, S(O)R³,C(S)R³, and S(O)₂R³.

In various embodiments, in the compound of Formula II, R⁸ and R⁹ areindependently selected at each occurrence from hydrogen, heteroalkyl,alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl,and heterocycle.

In various embodiments, the compound of Formula II has the structure ofFormula II-A. In various embodiments, in the compound of Formula II-A,[MIFBM] and [IgGBM] are as defined herein.

A compound of Formula II-A, having the structure:

wherein:

[MIFBM/IgGBM] is a MIF or IgG Binding Moiety which binds respectively tocirculating MIF or IgG in a subject, each of which is related to adisease state or condition and is to be removed by action of hepatocytesor other cells of the subject;

[ASGPBM] is an asialoglycoprotein receptor binding moiety having thestructure selected from

each [CON] is an optional connector chemical moiety which, when present,connects the [LIN] to [CPBM] or to [ASGPBM];

[LIN] is [LINKER] or [LINKER-2], each of which is a chemical moietyhaving a valency from 1 to 15, which covalently attaches to one or more[ASGPBM] or [CPBM] groups, optionally through a [CON], wherein the [LIN]optionally itself contains one or more [CON] groups;

Z_(B) is absent, (CH₂)_(IM), C(O)—(CH₂)_(IM)—, orC(O)—(CH₂)_(IM)—NR_(M);

R_(M) is H or a C₁-C₃ alkyl group optionally substituted with one or twohydroxyl groups;

R₂ is

wherein R^(AM) is H, C₁-C₄ alkyl optionally substituted with up to 3halo groups and one or two hydroxyl groups, —(CH₂)_(K)COOH,—(CH₂)_(K)C(O)O—(C₁-C₄ alkyl) optionally substituted with 1-3 halogroups, —O—C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3 halogroups, —C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3 halo groups,or —(CH₂)_(K)—NR^(N3)R^(N4), or

R₂ is

wherein

-   -   R^(TA) is H, CN, NR^(N1)R^(N2), —(CH₂)_(K)OH, —(CH₂)_(K)O(C₁-C₄        alkyl) optionally substituted with 1-3 halo groups, C₁-C₄ alkyl        optionally substituted with 1-3 halo groups, —(CH₂)_(K)COOH,        —(CH₂)_(K)C(O)O—(C₁-C₄ alkyl) optionally substituted with 1-3        halo groups, —O—C(O)—(C₁-C₄ alkyl) optionally substituted with        1-3 halo groups, or —C(O)—(C₁-C₄ alkyl) optionally substituted        with 1-3 halo groups, or    -   R^(TA) is a C₃-C₁₀ aryl or a three- to ten-membered heteroaryl        group containing up to 5 heteroaryl atoms, each of the aryl or        heteroaryl groups being optionally substituted with up to three        CN, NR^(N1)R^(N2), —(CH₂)_(K)OH, —(CH₂)_(K)O(C₁-C₄ alkyl)        optionally substituted with 1-3 halo groups, C₁-C₃ alkyl        optionally substituted with 1-3 halo groups or 1-2 hydroxy        groups, —O—(C₁-C₃-alkyl) optionally substituted from 1-3 halo        groups, —(CH₂)_(K)COOH, —(CH₂)_(K)C(O)O—(C₁-C₄ alkyl) optionally        substituted with 1-3 halo groups, O—C(O)—(C₁-C₄ alkyl)        optionally substituted with 1-3 halo groups, or        —(CH₂)_(K)C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3        halo groups, or    -   R^(TA) is

optionally substituted with up to three C₁-C₃ alkyl groups which areoptionally substituted with up to three halo groups; or

-   -   R^(TA) is

D. Other-Based ASGPR-Binding Moieties

In some embodiments, the ASGPR binding moieties can be any of themoieties described in: Reshitko, G. S., et al., “Synthesis andEvaluation of New Trivalent Ligands for Hepatocyte Targeting via theAsialoglycoprotein Receptor,” Bioconjugate Chem, doi:10.1021/acs.bioconjchem.0c00202; Majouga, A. G., et al., “Identificationof Novel Small-Molecule ASGP-RLigands,” Current Drug Delivery, 2016, 13,1303-1312, doi: 10.2174/1567201813666160719144651; Olshanova, A. S., etal., “Synthesis of a new betulinic acid glycoconjugate withN-acetyl-D-galactosamine for the targeted delivery to hepatocellularcarcinoma cells,” Russian Chemical Bulletin, International Edition, Vol.69, No. 1, pp. 158-163, January 2020; Yamansarov, E. Yu., et al., “NewASGPR-targeted ligands based on glycoconjugated natural triterpenoids,”Russian Chemical Bulletin, International Edition, Vol. 68, No. 12, pp.2331-2338, December 2019; Congdon, M. D., et al., “Enhanced Binding andReduced Immunogenicity of Glycoconjugates Prepared via Solid-StatePhotoactivation of Aliphatic Diazirine Carbohydrates,” BioconjugateChem, doi: 10.1021/acs.bioconjchem.0c00555; and Dhawan, V., et al.,“Polysaccharide conjugates surpass monosaccharide ligands inhepatospecific targeting—Synthesis and comparative in silico and invitro assessment,” Carbohydrate Research 509 (2021) 108417, doi:10.1016/j.carres.2021.108417. The following ASGPR binding moieties areillustrative and not intended to be limiting.

1. GalNAc-Tyrosine Based Moieties

In some embodiments, the ASGPR binding moiety can be a moiety having thestructure of M1, M2, M3, or M4, or a combination thereof. In thestructures of M1, M2, M3, and M4, X is independently at each occurrenceO, NH, or S. In various embodiments, compounds of Formula I or FormulaII can have one, two, or three ASGPR binding moieties with the structureof M1, M2, M3, or M4.

In various embodiments, ASGPR binding moieties M1 to M4 can beconjugated to any suitable [CON], [Linker], or [Linker-2] as describedherein and in Congdon, M. D., et al., “Enhanced Binding and ReducedImmunogenicity of Glycoconjugates Prepared via Solid-StatePhotoactivation of Aliphatic Diazirine Carbohydrates,” BioconjugateChem, doi: 10.1021/acs.bioconjchem.0c00555.

2. Trivalent Triazole-Based Moieties

In some embodiments, the ASGPR binding moiety can be a moiety having thestructure of M5:

In the structures M5, each R is independently at each occurrence R₁ orR₂,

In various embodiments, compounds of Formula I or Formula II contain anASGPR binding moiety with the structure of M5. In various embodiments,each R in M5 is R₁. In various embodiments, each R in M5 is R₂.

In various embodiments, ASGPR binding moiety M5 can be conjugated/bondedto any suitable [CON], [Linker], or [Linker-2] as described herein andin Reshitko, G. S., et al., “Synthesis and Evaluation of New TrivalentLigands for Hepatocyte Targeting via the Asialoglycoprotein Receptor,”Bioconjugate Chem, doi: 10.1021/acs.bioconjchem.0c00202.

3. Galactose- and Agarose-derived Behenic Acid Ester Moieties

In various embodiments, the ASGPR binding moiety can be the galactosebehenic acid ester-derived moiety M7:

In the structure M7, Y is OH or NHAc.

In various embodiments, the ASGPR binding moiety can be the agarosebehenic acid ester-derived moiety M8:

In various embodiments, ASGPR binding moieties M7 and M8 can beconjugated to any suitable [CON], [Linker], or [Linker-2] as describedherein and in Dhawan, V., et al., “Polysaccharide conjugates surpassmonosaccharide ligands in hepatospecific targeting—Synthesis andcomparative in silico and in vitro assessment,” Carbohydrate Research509 (2021) 108417, doi: 10.1016/j.carres.2021.108417.

4. Other Small Molecule ASGPR Binding Moieties

In various embodiments, the ASGPR binding moiety can be any of thecompounds 2-18 below:

In various embodiments, in compounds 15 and 16, R is CH₂OAc, COOH, orCH₂OH. Compounds 2-18 can be conjugated/bonded to any suitable [CON],[Linker], or [Linker-2] as described herein and in Majouga, A. G., etal., “Identification of Novel Small-Molecule ASGP-R Ligands,” CurrentDrug Delivery, 2016, 13, 1303-1312, doi:10.2174/1567201813666160719144651; Olshanova, A. S., et al., “Synthesisof a new betulinic acid glycoconjugate with N-acetyl-D-galactosamine forthe targeted delivery to hepatocellular carcinoma cells,” RussianChemical Bulletin, International Edition, Vol. 69, No. 1, pp. 158-163,January 2020; Yamansarov, E. Yu., et al., “New ASGPR-targeted ligandsbased on glycoconjugated natural triterpenoids,” Russian ChemicalBulletin, International Edition, Vol. 68, No. 12, pp. 2331-2338,December 2019. Compounds 2-18 can be attached through any suitablereactive group contained therein. Without limitation, compounds 2-13 canbe attached to a CON], [Linker], or [Linker-2] through or by reactionwith at least one OH, NH, vinyl, alkynyl, amide, acid, ester, ketone, oraromatic halogen contained in compounds 2-18. Suitable reaction modesfor attaching compounds 2-18 to a [CON], [Linker], or [Linker-2] asdescribed herein include, but are not limited to, substitution (e.g.alkylation of OH or NH groups), esterification (forming an ester),amidation (forming an amide), transesterification (exchanging one esterfor another), transamidation (exchanging one amide for another),azide-alkyne cycloaddition, and other reactions capable of forming C—C,N—C, or O—C bonds with vinyl and alkynyl groups such as cycloadditions,aminations, oxidations, alkylations, rearrangement reactions (e.g.Claisen, Cope, etc.), and the like.

The term “pharmaceutically acceptable salt” or “salt” is used throughoutthe specification to describe a salt form of one or more of thecompositions herein which are presented to increase the solubility ofthe compound in saline for parenteral delivery or in the gastric juicesof the patient's gastrointestinal tract in order to promote dissolutionand the bioavailability of the compounds. Pharmaceutically acceptablesalts include those derived from pharmaceutically acceptable inorganicor organic bases and acids. Suitable salts include those derived fromalkali metals such as potassium and sodium, alkaline earth metals suchas calcium, magnesium and ammonium salts, among numerous other acidswell known in the pharmaceutical art. In some embodiments, sodium andpotassium salts are used as neutralization salts of carboxylic acids andfree acid phosphate containing compositions according to the presentdisclosure. The term “salt” shall mean any salt consistent with the useof the compounds according to the present disclosure. In the case wherethe compounds are used in pharmaceutical indications, including thetreatment of prostate cancer, including metastatic prostate cancer, theterm “salt” shall mean a pharmaceutically acceptable salt, consistentwith the use of the compounds as pharmaceutical agents.

The term “coadministration” shall mean that at least two compounds orcompositions are administered to the patient at the same time, such thateffective amounts or concentrations of each of the two or more compoundsmay be found in the patient at a given point in time. Although compoundsaccording to the present disclosure may be co-administered to a patientat the same time, the term embraces both administration of two or moreagents at the same time or at different times, provided that effectiveconcentrations of all coadministered compounds or compositions are foundin the subject at a given time. Chimeric antibody-recruiting compoundsaccording to the present disclosure may be administered with one or moreadditional anti-cancer agents or other agents which are used to treat orameliorate the symptoms of cancer, especially prostate cancer, includingmetastatic prostate cancer.

The term “anticancer agent” or “additional anticancer agent” refers to acompound other than the chimeric compounds according to the presentdisclosure which may be used in combination with a compound according tothe present disclosure for the treatment of cancer. Exemplary anticanceragents which may be coadministered in combination with one or morechimeric compounds according to the present disclosure include, forexample, antimetabolites, inhibitors of topoisomerase I and II,alkylating agents and microtubule inhibitors (e.g., taxol), amongothers. Exemplary anticancer compounds for use in the present disclosuremay include everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101,pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886),AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197,MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFRinhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1modulator, a Bcl-2 inhibitor, an HDAC inhibitor, a c-MET inhibitor, aPARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TKinhibitor, an anti-HGF antibody, a PI3 kinase inhibitors, an AKTinhibitor, a JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, a focaladhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a VEGFtrap antibody, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib,panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171,batabulin, ofatumumab (Arzerra), zanolimumab, edotecarin, tetrandrine,rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol,Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide,gimatecan, IL13-PE38QQR, INO 1001, IPdR₁ KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan,Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat,etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin,5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709,seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258);3-[5-(methylsulfonylpiperadinemethyl)-indolylj-quinolone, vatalanib,AG-013736, AVE-0005, the acetate salt of [D-Ser(But) 6, Azgly 10](pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH₂ acetate[C₅₉H₈₄N₁₈Oi₄-(C₂H₄O₂)_(X) where x=1 to 2.4], goserelin acetate,leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate,hydroxyprogesterone caproate, megestrol acetate, raloxifene,bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714;TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody,erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662,tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid,valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951,aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, BacillusCalmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan,carboplatin, carmustine, chlorambucil, cisplatin, cladribine,clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin,daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox, gefitinib, bortezimib, paclitaxel, irinotecan,topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonalantibody) and erbitux, cremophor-free paclitaxel, epithilone B,BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene,ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene,TSE-424, HMR-3339, ZK186619, PTK787/ZK 222584, VX-745, PD 184352,rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573,RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684,LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonists,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin,epoetin alfa and darbepoetin alfa, vemurafenib among others, includingimmunotherapy agents such as IDO inhibitors (an inhibitor of indoleamine2,3-dioxygenase (IDO) pathway) such as Indoximod (NLG-8187), Navoximod(GDC-0919) and NLG802, PDL1 inhibitors (an inhibitor of programmeddeath-ligand 1) including, for example, nivolumab, durvalumab andatezolizumab, PD1 inhibitors such as pembrolizumab (Merck) and CTLA-4inhibitors (an inhibitor of cytotoxic T-lymphocyte associated protein4/cluster of differentiation 152), including ipilimumab andtremelimumab, among others.

In addition to anticancer agents, a number of other agents may becoadministered with chimeric compounds according to the presentdisclosure in the treatment of cancer. These include active agents,minerals, vitamins and nutritional supplements which have shown someefficacy in inhibiting cancer tissue or its growth or are otherwiseuseful in the treatment of cancer. For example, one or more of dietaryselenium, vitamin E, lycopene, soy foods, curcumin (turmeric), vitaminD, green tea, omega-3 fatty acids and phytoestrogens, includingbeta-sitosterol, may be utilized in combination with the presentcompounds to treat cancer.

Without not being limited by way of theory, compounds according to thepresent disclosure which contain a MIF binding moiety (MIFBM) orantibody binding moiety and ASGPR binding moiety selectively bind toliver cells and through that binding, facilitate the introduction of theMIFBM group into hepatocytes which bind the ASGPRBM selectively, where,the MIF protein, inside the hepatocyte is degraded and removed fromcirculation. Thus, compounds according to the present disclosure bothbind to MIF proteins and remove the MIF proteins from circulationresulting in a dual action which is particularly effective for treatingdisease states and conditions.

Pharmaceutical compositions comprising combinations of an effectiveamount of at least one compound disclosed herein, often a bi-functionalchimeric compound (containing at least one MIFBM group or antibodybinding moiety and at least one ASGPRBM) according to the presentdisclosure, and one or more of the compounds as otherwise describedherein, all in effective amounts, in combination with a pharmaceuticallyeffective amount of a carrier, additive or excipient, represents afurther aspect of the present disclosure. These may be used incombination with at least one additional, optional anticancer agent asotherwise disclosed herein.

The compositions of the present disclosure may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers and may also be administered in controlled-releaseformulations. Pharmaceutically acceptable carriers that may be used inthese pharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as prolaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

In some embodiments, the compositions of the present disclosure areadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir,among others. The term “parenteral” as used herein includessubcutaneous, intravenous, intramuscular, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques. In some embodiments,the compositions are administered orally (including via intubationthrough the mouth or nose into the stomach), intraperitoneally orintravenously.

Sterile injectable forms of the compositions of this disclosure may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1, 3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such as Ph. Helv orsimilar alcohol.

The pharmaceutical compositions of this disclosure may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this disclosure may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this disclosure may also beadministered topically, especially to treat skin cancers, psoriasis orother diseases which occur in or on the skin. Suitable topicalformulations are readily prepared for each of these areas or organs.Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-acceptable transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this disclosure include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater.

Alternatively, the pharmaceutical compositions can be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or assolutions in isotonic, pH adjusted sterile saline, either with ourwithout a preservative such as benzylalkonium chloride. Alternatively,for ophthalmic uses, the pharmaceutical compositions may be formulatedin an ointment such as petrolatum.

The pharmaceutical compositions of this disclosure may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of compound in a pharmaceutical composition of the instantdisclosure that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host and diseasetreated, the particular mode of administration. In some embodiments, thecompositions are formulated to contain between about 0.05 milligram toabout 1.5 grams, from 0.1 milligram to 1 gram, 0.5 milligram to 750milligrams, more often about 1 milligram to about 600 milligrams, andeven more often about 10 milligrams to about 500 milligrams of activeingredient, alone or in combination with at least one additionalcompound which may be used to treat cancer, prostate cancer ormetastatic prostate cancer or a secondary effect or condition thereof.

Methods of treating patients or subjects in need for a particulardisease state or condition as otherwise described herein, especiallycancer, comprise administration of an effective amount of apharmaceutical composition comprising therapeutic amounts of one or moreof the novel compounds described herein and optionally at least oneadditional bioactive (e.g., anti-cancer, anti-inflammatory) agent. Theamount of active ingredient(s) used in the methods of treatment of theinstant disclosure that may be combined with the carrier materials toproduce a single dosage form will vary depending upon the host treated,the particular mode of administration. For example, the compositionscould be formulated so that a therapeutically effective dose of betweenabout 0.01, 0.1, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,70, 75, 80, 85, 90 or 100 mg/kg of patient/day or in some embodiments,greater than 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200mg/kg of the novel compounds can be administered to a patient receivingthese compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease or condition beingtreated.

A patient or subject (e.g. a human) suffering from an autoimmunedisease, an inflammatory disease or cancer can be treated byadministering to the patient (subject) an effective amount of achimeric/bi-functional compound according to the present disclosureincluding pharmaceutically acceptable salts, solvates or polymorphs,thereof optionally in a pharmaceutically acceptable carrier or diluent,either alone, or in combination with other known pharmaceutical agents,exemplary agents which can assist in treating autoimmune and/orinflammatory diseases or cancer, including metastatic cancer orrecurrent cancer or ameliorating the secondary effects and/or symptomsassociated with these disease states and/or conditions. This treatmentcan also be administered in conjunction with other conventionaltherapies, such as radiation treatment or surgery for cancer.

The present compounds, alone or in combination with other agents asdescribed herein, can be administered by any appropriate route, forexample, orally, parenterally, intravenously, intradermally,subcutaneously, or topically, in liquid, cream, gel, or solid form, orby aerosol form.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount for the desired indication, withoutcausing serious toxic effects in the patient treated. An exemplary doseof the active compound for all of the herein-mentioned conditions is inthe range from about 10 ng/kg to 300 mg/kg, such as 0.1 to 100 mg/kg perday, such as 0.5 to about 25 mg per kilogram body weight of therecipient/patient per day. Some exemplary dosages will range from about0.01-3% wt/wt in a suitable carrier.

The compound is conveniently administered in any suitable unit dosageform, including but not limited to one containing less than 1 mg, 1 mgto 3000 mg, such as 5 to 500 mg of active ingredient per unit dosageform. An oral dosage of about 25-500 mg is often convenient.

The active ingredient is sometimes administered to achieve peak plasmaconcentrations of the active compound of about 0.00001-30 mM, such asabout 0.1-30 μM. This may be achieved, for example, by the intravenousinjection of a solution or formulation of the active ingredient,optionally in saline, or an aqueous medium or administered as a bolus ofthe active ingredient. Oral administration is also appropriate togenerate effective plasma concentrations of active agent.

The concentration of active compound in the drug composition will dependon absorption, distribution, inactivation, and excretion rates of thedrug as well as other factors known to those of skill in the art. It isto be noted that dosage values will also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed composition. The active ingredient may be administered atonce, or may be divided into a number of smaller doses to beadministered at varying intervals of time.

Oral compositions will generally include an inert diluent or an ediblecarrier. They may be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound or its prodrug derivative can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Pharmaceuticallycompatible binding agents, and/or adjuvant materials can be included aspart of the composition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a dispersing agent such as alginicacid, Primogel, or corn starch; a lubricant such as magnesium stearateor Sterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring. When the dosage unitform is a capsule, it can contain, in addition to material of the abovetype, a liquid carrier such as a fatty oil. In addition, dosage unitforms can contain various other materials which modify the physical formof the dosage unit, for example, coatings of sugar, shellac, or entericagents.

The active compound or pharmaceutically acceptable salt thereof can beadministered as a component of an elixir, suspension, syrup, wafer,chewing gum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors

The active compound or pharmaceutically acceptable salts thereof canalso be mixed with other active materials that do not impair the desiredaction, or with materials that supplement the desired action, such asother anticancer agents, anti-inflammatory agents, immunosuppressants,antibiotics, antifungals, or antiviral compounds. In certain aspects ofthe disclosure, one or more chimeric/bi-functional MIF binding compoundaccording to the present disclosure is coadministered with anotheranticancer agent and/or another bioactive agent, as otherwise describedherein.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parental preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

If administered intravenously, carriers sometimes are physiologicalsaline or phosphate buffered saline (PBS).

In certain embodiments, the active compounds are prepared with carriersthat will protect the compound against rapid elimination from the body,such as a controlled and/or sustained release formulation, includingimplants and microencapsulated delivery systems. Biodegradable,biocompatible polymers can be used, such as ethylene vinyl acetate,polyanhydrides, polyglycolic acid, collagen, polyorthoesters, andpolylactic acid. Methods for preparation of such formulations will beapparent to those skilled in the art.

Liposomal suspensions or cholestosomes may also be pharmaceuticallyacceptable carriers. These may be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811 (which is incorporated herein by reference in its entirety).For example, liposome formulations may be prepared by dissolvingappropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine,stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, andcholesterol) in an inorganic solvent that is then evaporated, leavingbehind a thin film of dried lipid on the surface of the container. Anaqueous solution of the active compound are then introduced into thecontainer. The container is then swirled by hand to free lipid materialfrom the sides of the container and to disperse lipid aggregates,thereby forming the liposomal suspension.

Chemical Synthesis

FIGS. 1, 7, and 13 attached hereto identifies exemplary compoundsaccording to the present disclosure which exhibit activity in binding toand reducing and/or eliminating unwanted circulating proteins fortherapeutic and/or diagnostic purposes. These compounds are based uponan MIF, anti-DNP IgG, or IgG binding moiety to which is covalentlyattached an ASPGR group such as GN₃ or AcF3-3 group through a linkerwhich contains from 1 to 100 ethylene glycol groups, more often from 1to 15 ethylene glycol groups, from 1 to 10 ethylene glycol groups, oftenfrom 2 to 10 ethylene glycol groups which are optionally attachedthrough a [CON] group, such as a 1,2,3-triazole or other [CON] group asdescribed herein.

FIG. 16 shows the synthesis of azide/amide carboxylic end capped PEGlinker intermediates which may be condensed onto an alkynyl precursor(e.g. NVS alkyne precursor of FIG. 5 ) to provide carboxylic acid cappedintermediate which can be used to provide bifunctional molecules.

FIG. 17 describes a general method for conversion of PEG molecules intohydroxyl azides. The PEG compound is tosylated (TsCl, DCM, in thepresence of base) at reduced temperature and further reacted with sodiumazide at elevated temperature in a non-nucleophilic solvent. The finalazidoalcohol is used in subsequent figures.

FIG. 18 describes the synthesis of a mesylated azide from a starting PEGmolecule employing the same synthetic steps to reach the intermediateazido alcohol. This is then treated with MsCl in pyridine to afford thefinal compound.

FIG. 19 shows the synthesis of the GalNAc ASGPR ligand linked throughPEG to a terminating amine. Pentaacetyl galactosamine is reacted withTMSOTf at elevated temperature in DCE to produce a bicyclicintermediate, which is then reacted with an azido alcohol to give anazide intermediate (TMSOTf, DCE). This molecule is then subjected to aStaudinger reduction to give an amine which is used in subsequentfigures.

FIG. 20 shows the synthesis of a higher affinity bicylic ASGPR ligand.Galactose pentaacetate is treated with HBr/AcOH to give the brominatedintermediate, which is treated with Zn and CuSO4 (water/AcOH) to givethe galactal. This is treated with ammonium cerium nitrate and sodiumazide at reduced temperature (MeCN) to give the disubstitutedintermediate compound. This is then treated with strong base(NaOMe/MeOH) to give the triol azide intermediate. This compound issilylated completely (TMSCl/pyr) then the primary alcohol is deprotected(potassium carbonate, MeOH, lowered temperature) and oxidized(Dess-Martin Periodinane, DCM). Treatment with strong base (NaOEt/HOEt)and paraformaldehyde gives the tetraol intermediate, which is cyclizedin strong acid (H2SO4/water) to give the bicyclic azide ligand.

FIG. 21 shows the synthesis of a trifluoro-acetate derivative of thebicyclic ASGPR ligand. The triol azide is reduced (Pd/C, MeOH) to givethe intermediate amine, which is then peracylated with trifuloroaceticanhydride. The esters are hydrolyzed with strong base (NaOMe/HOMe) togive the intermediate amide, which is protected using dimethoxypropanein the presence of camphorsulfonic acid in DMF at elevated temperature.This is then reacted a mesylated azdio alcohol in the presence of strongbase (NaH/DMF) to give an intermediate azide that is reduced (Lindlar'scatalyst, MeOH) to give the final amine.

FIG. 22 shows the synthesis of the MIF-targeting linker to a monovalentlinker, which is synthesized through analagous methods as described in aprevious figure. The boc-protected methyl ester is deprotected with TFAin DCM, then coupled to the MIF-targeting carboxylic acid (HBTU, DIPEA,DMF). Subsequent hydrolysis with strong base (NaOH/dioxane/H2O) givesthe MIF-targeting carboxylic acid.

FIG. 23 shows the synthesis of the di-carboxylic acid MIF targetingmotif, which is synthesized as described in previous figures.

FIG. 24 shows the synthesis of a tris base-derived trivalent linker.Tris base is treated with di-t-butyl dicarbonate in the presence of baseto give the boc protected triol, which is then reacted withacrylonitrile in the presence of base (dioxane/H2O) to give a trinitrileintermediate. This is then converted to the methyl ester throughtreatment with strong acid in methanol. The amine is then reacted withCbz-glycine through a DCC-mediated amide formation, and deprotected togive a tricarboxylic acid that is used in subsequent figures.

FIG. 25 describes the synthesis of an ASGPR-targeting moiety employingthree GalNAc ASGPR ligands. The tricarboxylic acid is reacted withamine-terminated protected GalNAc (amide bond formation in the presenceof HBTU and DIPEA), then deprotected by reduction (Pd/C, solvent) andtreatment with strong base (NaOMe/MeOH).

FIG. 26 shows the synthesis of the tri-carboxylic acid MIF targetingmotif, which is synthesized as described in previous figures.

FIG. 27 shows the synthesis of the MIF NVS alkyne precursor which can bereacted with an azido reactant containing a carboxylic acid (as setforth in subsequent figures) to provide MIF-NVS-carboxylic acid cappedreactants to produce the bifunctional compounds.

FIG. 28 shows the synthesis of the MIF-targeting moiety terminating in acarboxylic acid. 2-chloroquinolin-6-ol is reacted with ethyl4-bromobutanoate in the presence of base (DMF, elevated temperature) togive an aryl chloride that then undergoes Sonogashira coupling atelevated temperature with ethynyltrimethylsilane. The intermediatesilylated compound is deprotected with TBAF (DCM/THF). A click reactionthen forms a triazole between the alkyne intermediate and in situsynthesized 4-azido-2-fluorophenol to give an ethyl ester intermediatethat is hydrolyzed with strong base (NaOH/dioxane) to give thecarboxylic acid that is used in subsequent figures.

FIG. 29 describes the synthesis of the bifunctional moleculeMIF-NVS-PEGn-GN3 through HBTU-mediated coupling in DMF of theASPGR-targeting amine and the MIF targeting carboxylic acid prepared byfirst forming the MIF-targeting carboxylic acid by condensing thereactant azido PEG-carboxylic acid onto the MIF moiety containing aalkyne terminated PEG group.

FIG. 30 describes the synthesis of bifunctional molecules MIF-GN3 andMIF-PEGn-GN3 through HATU-mediated coupling (DMF, DIPEA) ofASGPR-targeting amine and MIF-targeting carboxylic acid.

FIG. 31 describes the synthesis of the bifunctional molecule targetingMIF and ASGPR, containing one bicyclic ASGPR AcF3 ligands. MIF-bindingmono-carboxylic acid is treated with HBTU, DIPEA, the amine terminatedligand, and DMF to give the amide, which is then deprotected with 1M HClto give the final compound.

FIG. 32 describes the synthesis of the bifunctional molecule targetingMIF and ASGPR, containing two bicyclic ASGPr ligands. It is synthesizedas described above.

FIG. 33 describes the synthesis of the bifunctional molecule targetingMIF and ASGPR, containing three bicyclic ASGPr ligands. It issynthesized as described above.

FIG. 34 shows the synthesis of DNP-GN3. 2,4-dinitro chlorobenzene wastreated with an amino carboxylic acid in the presence of weak base togive the di-nitro analine carboxylic acid intermediate. Further stepswere carried out as described for previous molecules.

FIG. 35 shows the synthesis of DNP-AcF3-3, which was carried out withmethods analogous previous compounds.

FIG. 36 shows the synthetic scheme used to obtain IBA-GN3. Pentaethyleneglycol was treated with tosyl chloride in the presence of base to givethe mono-tosylated alcohol, which was then treated with sodium azide atelevated temperature to give the azidoalcohol. This compound was thenoxidized using Jones reagent, then reduced with Palladium on carbonunder hydrogen atmosphere to give a carboxylic acid-amine. Separately,indole butyric acid was treated with N-hydroxysuccinimide, EDC, andDIPEA to give the NHS-ester indole, which was then reacted with theabove carboxylic acid-amine. The product was again reacted withN-hydroxysuccinimide, EDC, and DIPEA to give a NHS ester. This NHS esterwas reacted with NH2-GN3, which was prepared as described previously.The subsequent amide was deprotected with NaOMe in MeOH to give compoundIBA-GN3.

FIG. 37 shows the synthesis of triazine-GN3. Cyanuric chloride wastreated with (4-(methoxycarbonyl)phenyl)methanaminium in THE anddiisopropylethlamine at −78° C. to give the mono-substituted product.This was then treated with cyclohexylmethanamine at room temperature toafford the second substitution. The final substitution was accomplishedunder elevated temperature with (1S,2S,4R)-bicyclo[2.2.1]heptan-2-amineto give the trisubstituted triazine. Deprotection with lithium hydroxidefollowed by amide coupling with a monoprotected diamine gave theBoc-protected derivative, which was deprotected and reacted withglutaric anhydride to give a carboxylic acid that was converted to anNHS ester using standard coupling conditions. This was reacted withNH2-GN3 to give the final product.

FIG. 38 shows the synthetic scheme used to access FcIII-GN3. The hexynylpeptide was prepared using standard solid phase peptide synthesistechniques. The peptide was removed from Rink resin using Reagent L,then oxidized using ammonium bicarbonate buffer (pH8-9) in MeOH underair to give the cyclic peptide. The peptide was reacted with GN3-azide,which was described previously, to give the product triazole FcIII-GN3.

FIG. 39 shows the synthetic scheme used to access FcIII-4c-GN3, whichwas accomplished using methods described above.

FIGS. 40-43 describe the synthesis of bifunctional molecules targetingMIF and ASGPr, containing three bicyclic ASGPR ligands with differentsubstitutions on the 2-amine of the sugar. They are synthesized throughanalagous methods described above as set forth in the attached figures.

FIG. 44 shows the synthesis of compound MIF-18-3. Tri-acyl galactal wasdeprotected with ammonia in methanol, then tri-benzyl protected withbenzylbromide in the presence of base. The alkene was hydrolyzedovernight with HCl in THF/H2O, then oxidized with PCC to give analdehyde. Sodium azide was then added alpha to the carbonyl with KHMDSand TIBSN3 at lowered temperature. The intermediated was then treatedwith p-OMePhMgBr in THE and toluene to give an intermediate alcohol,which was then reduced using Et3SiH in the presence of BF3-Et2O atreduced temperature. The resulting azide was then reduced with Lindlar'scatalyst under a hydrogen atmosphere to give the corresponding amine,which was acylated with trifluoroacetic acid in pyridine. The benzylgroups were then removed with Pd(OH2) on carbon in MeOH at reflux, andthe resulting tri-ol protected as an acetal with dimethoxypropane andcamphorsulfonic acid at elevated temperature. The remainder of thesynthesis was carried out as described for previous molecules.

FIG. 45 shows the synthesis of compound MIF-31-3. Galactosaminehydrochloride was fully protected with acetic anhydride, then treatedwith allyl alcohol in the presence of BF3 ehtrate to give the allylintermediate. Treatment with pivaloyl chloride in pyridine gave a di-Pivprotected intermediate, which was treated with triflic anhydride andsubsequently subjected to hydrolysis in water at elevated temperature.The pivaloyl groups were removed by treatment with NaOMe in MeOH to givethe allyl triol intermediate. Subsequent steps were performed asdescribed for previous molecules.

FIG. 46 shows the synthesis of compound MIF-15-3, which was synthesizedusing procedures analogous to compounds described above.

FIG. 47 shows the synthesis of compound MIF-19-3. The molecule issynthesized through a late stage triazole-forming click reaction betweenthe triazide and propiolic acid in methanol in the presence of THPTA,copper sulfate, water, and sodium ascorbate. All other reactions areperformed as described above.

FIG. 48 shows the synthesis of compound MIF-16-3, which was synthesizedusing procedures analogous to compounds described above.

FIG. 49 shows the synthesis of compound MIF-20-3, which was synthesizedusing procedures analogous to compounds described above.

FIG. 50 shows the synthesis of compound MIF-14-3, which was synthesizedusing procedures analogous to compounds described above.

FIG. 51 shows the synthesis of compound MIF-21-3, which was synthesizedusing procedures analogous to compounds described above.

FIGS. 52-66 show the synthesis of a number of MIF-binding compounds withvarious ASGPRBM moieties. These are synthesized through methodsanalogous to those laid out above.

EXAMPLES

The instant specification further describes in detail by reference tothe following experimental examples. These examples are provided forpurposes of illustration only, and are not intended to be limitingunless so specified. Thus, the instant specification should in no way beconstrued as being limited to the following examples, but rather, shouldbe construed to encompass any and all variations which become evident asa result of the teaching provided herein.

Proper protein section and turnover is a necessary process formaintaining homeostasis. Newly synthesized proteins targeted forsecretion are first trafficked to the endoplasmic reticulum, where theyare post-translationally modified with N-linked glycan chainsterminating in sialic acids (1). As proteins age, terminal sialic acidresidues are removed by circulating endogenous glycosydases (2). Thisnatural protein aging process unmasks galactose and N-acetylgalactose(GalNAc) residues, which bind the asialoglycoprotein receptor (ASGPR) onthe surface of hepatocytes (3-5).

The ASGPR is a C-type lectin that removes aged circulating proteins withexposed GalNAc residues from circulation by trafficking them tolysosomes. Multiple galactose or GalNAc residues displayed on theprotein surface are necessary for high-affinity binding to—andsubsequent endocytosis by—ASGPR (6, 7). Once these proteins areendocytosed, they are released from the ASGPR through depletion ofcalcium from the endosome and changes in binding site amino acidprotonation changes due to a decrease in pH (12); the ASGPR is recycledback to the hepatocyte surface (13). Endocytosed proteins are traffickedto late endosomes, which are fused with lysosomes. Lysosomal proteasesthen degrade endocytosed proteins, permanently removing them fromcirculation (14).

Non-glycosylated proteins are not known to be natural target for theASGPR. One such protein is macrophage inhibitory factor (MIF), a 12.5kDa protein with possible catalytic activity (15). Genetic depletion orantibody neutralization of MIF has been shown to have positive resultsin models of sepsis (16), multiple schlorosis (17), rheumatoid arthritis(18), and burn recovery (21). A bifunctional molecule for degradingcirculating MIF that takes advantage of ASGPR as an entryway forproteins into the endosomal-lysosomal degradation pathway was proposed.The bicyclic ASGPR-binding molecules in MIF-AcF2 and MIF-AcF3 have beenreported previously as high affinity binders for the ASGPR (22, 23).

Example 1: Biological Data

In Example 1, exemplary compounds according to some embodiments weretested to determine their biological activity. Active compounds areshown in FIGS. 1, 7 and 13 hereof. The results of the biologicalexperiments are described herein below.

FIG. 1 shows exemplary compounds according to the present disclosure.Note that the figure discloses compound 3w (negative control for MIFinhibition), MIF-NVS-PEGnGN3, MIFGN3, MIF-PEGnGN3, MIF-AcF3-1,MIF-AcF3-2 and MIF-AcF3-3. Note that n in the PEG linker sometimesranges from 1-12, such as 1 to 10, 2 to 8, 2 to 6, 2 to 5 or 1, 2, 3 or4.

In an experiment the results of which are shown in FIG. 2 , A.fluorescence polarization data of MIF-FITC binding to human MIFindicates that the MIF-binding moiety of the present disclosure bindsMIF. B. Bifunctional molecules WJ-PEG4-GN3, WJ-PEG2-GN3, andNVS-PEG3-GN3 bound competitively with MIF-FITC, indicating that thebifunctional molecules maintain the ability to bind human MIF.

In an experiment the results of which are presented in FIG. 3 ,bifunctional molecules were able to deplete human MIF from thesupernatant of culture HepG2 cells. Briefly, human MIF (100 nM) wasadded to cell culture media in the presence of negative control MIFinhibitor 3w as well as bifunctional molecules MIF-NVS-PEGn-GN3,MIF-GN3, MIF-PEGn-Gn3, MIF-AcF3-1, MIF-AcF3-2, and MIF-AcF3-3. Allmolecules utilized a known MIF-binding ligand. Experiments wereperformed in 96 well plates (approximate surface area 0.3 cm²). HepG2cells were grown to 90% confluency in RPMI media, then washed with PBS(2×) and treated with serum-free media (optimem+0.1% BSA, +Pen/Strep)containing 100 nM huMIF (Cayman Chemical) and compounds (whenapplicable). Compounds were diluted from 1 mM stock solutions in DMSO.After 24 hours, a sample of the supernatant (2 uL) was collected,diluted 1:100, and analyzed for MIF content by sandwich ELISA (andincubated for 24 hours in the presence or absence of compound).Remaining MIF levels were determined by sandwich ELISA (biolegendmonoclonal anti-MIF and biotinylated anti-MIF antibodies). Datarepresents the average of at least 3 biological replicates, and errorbars represent a standard deviation. After 24 hours, up to 95.3% of theMIF had been depleted from cell culture media (in the case ofMIF-AcF3-3).

FIG. 4 shows the results of an experiment to determine whether or notMIF internalized by HepG2 cells is trafficked to lysosomes. In thisexperiment, cells were incubated with rhuMIF (Cayman) at a concentrationof 100 nM with 200 nM MIF-GN3. After 12 hours, cells were fixed withformaldehyde, permeabilized, and probed with anti-Lamp2 antibody (mousemonoclonal, Abcam), polyclonal rabbit anti-MIF antibody (Thermo) andwith Alexa-488 labeled anti-mouse antibody and Alexa 568-labeledanti-rabbit antibody, evidencing internalization in lysosomes.

FIG. 5 shows that MIF-GN3 mediates the depletion of injected human MIFfrom mice. Human MIF has a half-life of approximately 40 minutes inmice. In this experiment, human recombinant MIF (Cayman chemical) wasco-injected into mice with an anti-DNP IgG, which was used as aninjection positive control. In particular, nude mice were injected with5 μg recombinant human MIF and 200 μg anti-DNP IgG as an injectioncontrol (FIG. 4 ). MIF-GN₃ was then injected at the concentration shownand blood drawn every twenty minutes over the course of two hours. Serumwas diluted 1:100 and analyzed for MIF content by sandwich ELISA(biolegend monoclonal anti-MIF and biotinylated anti-MIF antibodies).The levels of the injected IgG were not significantly different betweentesting groups. In the mice treated with MIF-GN₃, a moderate increase inhuMIF levels up to 20 ng/ml was seen, while in mice injected with PBSnegative control, serum levels of up to 150 ng/ml were observed,evidencing a substantial decrease in huMIF levels as a consequence ofthe administration of MIF-GN₃.

FIG. 6 shows that MIF-GN3 is able to delay tumor growth in a mouse modelof prostate cancer. In this experiment, nude mice were engrafted withPC3 human prostate cancer cells. Treatment was then initiatedimmediately with either a non-bifunctional MIF inhibitor (3w), ananti-MIF antibody, or MIF-GN3. MIF-GN3 showed a slowing of tumor growthover the course of the experiment, comparable to the MIF-neutralizingantibody. 3w did not inhibit tumor growth, validating the necessity ofdegrading MIF for therapeutic efficacy.

FIG. 7 shows molecules DNP-GN3 and DNP-AcF3-3, which are bifunctionalmolecules that bind to anti-DNP IgG and ASGPR. These compounds were usedin several of the experiments as described below.

FIG. 8 shows that DNP-GN3 and DNP-AcF3-3 mediate the formation of aternary complex between HepG2 cells and anti-DNP, thus validating thebifunctional character of the molecules. In this experiment,ASGPR-expressing HepG2 cells were incubated with bifunctional moleculesand alexa-488 labeled anti-DNP (Thermo). The readout is meanfluorescence intensity of the cell population. Fluorescence was measuredusing a flow cytometer.

In a further experiment, the results presented in FIG. 9 show thatDNP-GN3 and DNP-AcF3-3 mediate the uptake of alexa 488-labeled anti-DNPby HepG2 cells. The assay carried out in this experiment was as isdescribed above for MIF uptake. Readout is percentage of Alexa488-positive cells after 6 hours. Fluorescence was measured using a flowcytometer.

FIG. 10 shows that DNP-GN3 and DNP-AcF3-3 mediate the localization ofalexa 568 labeled anti-DNP to late endosomes and lysosomes. Thisexperiment was carried out as described above for the MIF colocalizationstudies.

The experimental results presented in FIG. 11 show that DNP-AcF3-3mediates the degradation of alexa 488-labeled anti-DNP in HepG2 cells.In this experiment, cells were incubated with 1 uM alexa 488-labeledanti-DNP (Thermo) and 200 nM DNP-AcF3-3. Cells were lysed (RIPA in PBS,containing protease inhibitors) at the given time and assayed bySDS-PAGE gel. Readout is fluorescence of protein fragments.

The results presented in FIG. 12 evidence that DNP-GN3 mediates thedepletion of anti-DNP from mouse serum. Mice were injected with anti-DNPon day 0, then treated with the given compounds each day for 6 days.Serum IgG levels were measured by ELISA. DNP-(OH)₃ is used as anon-bifunctional control molecule.

FIG. 13 shows the structures of IgG-degrading molecules IBA-GN3,Triazine-GN3, FcIII-GN3, and FcIII-4c-GN3.

FIG. 14 shows that FcIII-GN3 mediates the uptake of human IgG into HepG2cells. This experiment was performed as described above.

FIG. 15 shows that FcIII-GN3 mediates the localization of IgG to lateendosomes in HepG2 cells. Experiment performed as described above.

Example 2: Experimental Chemistry

In Example 2, synthesis and characterization of exemplary compoundsaccording to some embodiments will be described.

Example 2-1. MIF Binding Molecule (FIG. 13) Example 2-1-1 MIF-1

2-chloroquinolin-6-ol (1.00 g, 5.57 mmol) and K₂CO₃ (1.53 g, 11.1 mmol,2.0 eq) were dissolved in DMF (20 mL). Ethyl bromobutyrate (1.63 g, 1.2mL, 8.35 mmol, 1.5 eq) was then added and the mixture stirred at 800 for12 hours. The reaction was diluted into ethyl acetate and washed withwater (2×) and brine (3×). The organic layer was dried over sodiumsulfate and evaporated to give compound 30, which was used in the nextstep without further purification.

¹H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J=8.6 Hz, 1H), 7.92 (d, J=9.2Hz, 1H), 7.40-7.32 (m, 2H), 7.07 (d, J=2.7 Hz, 1H), 4.20-4.09 (m, 5H),2.56 (t, J=7.2 Hz, 2H), 2.19 (t, J=6.7 Hz, 2H), 1.26 (t, J=7.1 Hz, 4H).

¹³C NMR (101 MHz, cdcl₃) δ 173.24, 157.46, 148.18, 143.87, 137.83,130.05, 128.06, 123.40, 122.67, 106.20, 77.48, 77.16, 76.84, 67.30,60.69, 30.87, 24.63, 14.39.

HRMS: [M+H]⁺ Expected 294.090, found 294.11

Example 2-1-2: MIF-2

Compound 30 (1.52 g, 5.17 mmol) was dissolved in THE (20 mL) andtriethylamine (2.88 mL, 20.7 mmol, 4 eq). Copper (I) iodide (49.0 mg,0.258 mmol, 0.05 eq), Pd(PPh₃)₂Cl₂ (181 mg, 0.258 mmol, 0.05 eq), andTMS-acetylene (1.07 mL, 762 mg, 7.75 mmol, 1.5 eq) were then added andthe reaction was stirred under pressure at 650 for 16 hours. Thereaction mixture was filtered through celite, washed ethyl acetate, andevaporated. The residue was purified on silica (50% ethyl acetate inhexanes) to give compound 31.

¹H NMR (500 MHz, Chloroform-d) δ 8.00 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.5Hz, 1H), 7.43-7.33 (m, 1H), 7.04 (d, J=2.2 Hz, 1H), 4.15 (dt, J=12.7,6.5 Hz, 4H), 2.56 (t, J=7.2 Hz, 2H), 2.24-2.13 (m, 2H), 1.26 (t, J=7.1Hz, 3H), 0.30 (s, 9H).

¹³C NMR (151 MHz, cdcl₃) δ 173.07, 124.73, 105.65, 67.11, 60.51, 30.67,24.42, 14.21, −0.27.

HRMS: [M+H]⁺ Expected 356.168, Found 356.505

Example 2-1-3: MIF-3

Procedure

Compound 31 (1.57 g, 4.42 mmol) was dissolved in DCM (45 mL) and TBAF(5.3 mL, 1M in THF, 5.30 mmol, 1.2 eq) was added dropwise. After 1minute of stirring 10% citric acid (50 mL) was added and the reactionstirred for 30 minutes. The organic phase was washed with water (1×),dried, and evaporated to give compound 32, which was used in the nextstep without further purification.

¹H NMR (600 MHz, Chloroform-d) δ 8.11-8.00 (m, 1H), 7.51 (d, J=8.4 Hz,1H), 7.38 (dd, J=9.3, 2.3 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 4.15 (p,J=6.6, 6.0 Hz, 3H), 3.43-3.36 (m, 1H), 2.56 (t, J=7.2 Hz, 1H), 2.22-2.14(m, 1H), 1.73-1.64 (m, 1H), 1.47 (q, J=7.4 Hz, 1H), 1.26 (t, J=7.1 Hz,2H), 1.02 (t, J=7.3 Hz, 1H).

CNMR: ¹³C NMR (151 MHz, cdcl₃) δ 173.06, 137.60, 129.91, 128.64, 124.50,123.18, 122.48, 105.99, 105.58, 77.20, 76.99, 76.77, 67.12, 60.51,59.14, 30.67, 24.42, 24.22, 19.80, 14.21, 13.69.

HRMS: [M+H]⁺ Expected 284.129, Found 284.327

Example 2-1-4: MIF-4

2-fluoro-4-iodophenol (126 mg, 0.529 mmol) and sodium azide (38 mg,0.528 mmol, 1.0 eq) were dissolved in DMSO (2.5 mL) and stirred for twohours at 70°. Compound 32 (150 mg, 0.529 mmol, 1 eq),trans-N,N′-dimethylcyclohexane-1,2-diamine (11 mg, 0.079 mmol, 0.15 eq),sodium ascorbate (10 mg, 0.053 mmol, 0.1 eq), copper (I) iodide (15 mg,0.079 mmol, 0.15 eq), and H₂O (2.5 mL) were then added, and the mixturestirred at 70° overnight. The reaction was diluted with ethyl acetateand washed with H₂O (1×) and brine (1×). The organic layer was driedover sodium sulfate, evaporated, and purified on silica (DCM/EtOAc) togive compound 33.

¹H NMR (600 MHz, DMSO-d₆) δ 10.46 (s, 1H), 9.32 (s, 1H), 8.39 (d, J=8.6Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.95 (dd, J=11.6, 2.6 Hz, 2H),7.77-7.71 (m, 1H), 7.43 (dd, J=4.8, 2.0 Hz, 2H), 7.16 (t, J=9.0 Hz, 1H),4.17 (d, J=6.3 Hz, 2H), 4.13-4.07 (m, 3H), 3.17 (d, J=5.2 Hz, 3H), 2.53(d, J=7.3 Hz, 3H), 2.07 (t, J=6.8 Hz, 2H), 1.19 (d, J=7.1 Hz, 3H), 0.94(d, J=7.3 Hz, 1H).

¹³C NMR (151 MHz, dmso) δ 172.96, 156.95, 151.95, 150.34, 148.62,145.98, 143.82, 136.47, 130.40, 129.01, 123.19, 121.83, 119.06, 118.62,117.31, 109.87, 109.72, 107.12, 67.43, 60.35, 49.03, 40.48, 40.36,40.22, 40.09, 39.95, 39.81, 39.67, 39.53, 30.61, 24.58, 23.48, 14.56,13.93.

HRMS: Expected 437.163, Found 437.164

Example 2-1-5: MIF-5

Compound 33 (90 mg, 0.206 mmol) was dissolved in dioxane (6 mL) and 2MNaOH (3 mL). The reaction was stirred for 2.5 hours at room temperature,at which time the reaction was diluted with water and the pH adjusted to3-4 with 1M HCl. The mixture was cooled to 4° and filtered to givecompound 34, which was used without further purification.

Example 2-2. GaINAc Spacer (FIG. 14)

Triethylene glycol (17.5 mL, 19.7 g, 131.13 mmol, 5 eq) was dissolved inDCM (150 mL) and trimethylamine (5.48 mL, 3.98 g, 1.5 eq) and cooled to0°. TsCl (5.00 g, 26.23 mmol, 1 eq) was then added and the reactionmixture stirred at room temperature for 18 hours. The reaction wasdiluted into DCM and washed with water (3×) and brine (1×). The organiclayer was dried over sodium sulfate and concentrated in vacuo. The crudeproduct was purified on silica (0-5% MeOH in DCM) to give compound 64(6.89 g, 22.6 mmol) in 85% yield.

¹H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J=8.3 Hz, 2H), 7.38-7.30 (m,2H), 4.23-4.14 (m, 2H), 3.71 (td, J=5.3, 4.3 Hz, 4H), 3.66-3.55 (m, 6H),2.45 (s, 3H).

¹³C NMR (101 MHz, cdcl₃) δ 144.98, 133.09, 129.95, 128.09, 72.58, 70.91,70.44, 69.28, 68.84, 61.88, 21.76.

Compound 64 (2.00 g, 6.57 mmol) and sodium azide (0.470 g, 7.23 mmol,1.1 eq) were dissolved in DMF (40 mL) and stirred overnight at 60°. 25mL of DMF was then removed by rotary evaporation, and the resultingmixture diluted into water and extracted with ethyl acetate (2×). Theorganic layers were washed with brine (3×), dried over sodium sulfate,and evaporated. The crude product was purified on silica (0-5% MeOH inDCM) to give compound 65 (932 mg, 5.32 mmol) in 81% yield.

Example 2-3. GaINAc ASGPR Ligand (FIG. 15)

Galactosamine pentaacetate (100 mg, 0.257 mmol) was dissolved indichloroethane (1 mL) and stirred at room temperature before theaddition of TMSOTf (70 uL, 86.0 mg, 0.387 mmol, 1.5 eq). The reactionwas stirred at 50° for 90 minutes, then allowed to cool to roomtemperature and stirred for a further 12 hours. The reaction was pouredinto ice cold saturated sodium bicarbonate and extracted into DCM. Theorganic layer was washed with water (2×), dried over sodium sulfate, andevaporated to give compound 66 (0.236 mmol, 77.7 mmol, 92%) as a darkgum, which was used without further purification.

¹H NMR (400 MHz, Chloroform-d) δ 5.98 (d, J=6.8 Hz, 1H), 5.45 (t, J=3.0Hz, 1H), 4.90 (dd, J=7.4, 3.3 Hz, 1H), 4.29-4.20 (m, 1H), 4.17 (d, J=6.9Hz, 1H), 4.10 (dd, J=11.1, 5.7 Hz, 1H), 3.99 (td, J=7.1, 1.4 Hz, 1H),2.11 (s, 3H), 2.05 (m, J=7.6 Hz, 6H).

¹³C NMR (101 MHz, cdcl₃) δ 170.46, 170.13, 169.78, 166.35, 121.82,118.64, 101.41, 71.76, 69.44, 65.25, 63.53, 61.56, 46.82, 20.77, 20.68,20.54, 14.41, 8.64, −0.06.

Compound 66 (200 mg, 0.607 mmol) and compound 65 (160 mg, 0.913 mmol,1.5 eq) were dissolved in 1,2-dichloroethane (5 mL). 4 Å molecularsieves were then added, and the reaction stirred for 30 minutes. TMSOTf(55 uL, 67.5 mg, 0.304 mmol, 0.5 eq) was then added to the mixture, andthe reaction stirred overnight. The mixture was diluted into DCM, washedwith 1M sodium bicarbonate (1×) and water (1×), then dried overmagnesium concentrate and concentrated. The crude oil was purified onsilica gel (50-100% EtoAc in DCM) to give compound 67 (245 mg, 0.486mmol) in 80.1% yield.

¹H NMR (400 MHz, Chloroform-d) δ 6.13 (d, J=9.3 Hz, 1H), 5.31 (dd,J=3.4, 1.1 Hz, 1H), 5.05 (dd, J=11.2, 3.4 Hz, 1H), 4.77 (d, J=8.6 Hz,1H), 4.28-4.04 (m, 3H), 3.93-3.79 (m, 3H), 3.78-3.58 (m, 8H), 3.43 (dt,J=28.2, 4.9 Hz, 4H), 2.15 (s, 3H), 2.04 (s, 3H) 1.98 (s, 3H), 1.97 (s,3H)

¹³C NMR (101 MHz, cdcl₃) δ 170.24, 170.09, 169.99, 101.84, 72.06, 71.27,70.50, 70.29, 70.27, 70.20, 70.00, 69.98, 69.67, 69.37, 68.18, 66.30,61.38, 61.17, 50.32, 50.26, 50.11, 22.80, 20.37, 20.31

HRMS: [M+Na]⁺ 527.207 found 527.203

Compound 67 (1.80 g, 3.57 mmol) was dissolved in THE (35 mL).Triphenylphosphine (1.40 g, 5.35 mmol, 1.5 eq) and water (257 uL, 14.28mmol, 4 eq) were then added and the reaction stirred at room temperatureunder nitrogen for 36 hours. The solvent was removed and the crudeproduct used in the next step without further purification.

Example 2-4. Tris Valent Glycine (FIG. 16)

Tris base (5.00 g, 41.3 mmol) was dissolved in dichloromethane (80 mL)and trimethylamine (20 mL). Di-tert-butyl dicarbonate (10.81 g, 49.6mmol, 1.2 eq) was then added, and the reaction stirred for 4 hours. Themixture was evaporated and the residue portioned between ethyl acetateand water. The organic fraction was washed with water (1×), 1M HCl (2×),saturated sodium bicarbonate (1×), and brine (1×) before drying oversodium sulfate and evaporation to give compound 23 (9.04 g, 40.9 mmol)in 99% yield, which was used without purification in further steps.

Compound 27 (9.04 g, 40.9 mmol) was dissolved in a mixture of dioxane(17 mL) and aqueous KOH (4.98 g, 88.7 mmol, 2.46 mL). Acrylonitrilte(8.84 mL, 7.16 g, 135.0 mmol, 3.3 eq) was then added dropwise over aperiod of 2.5 hours, and the reaction stirred under nitrogen for 24hours. The reaction was neutralized with the addition of 2M HCl (30 mL)and portioned between DCM and water. The organic layer was washed withwater (2×) and brine (1×), dried over sodium sulfate, and evaporated.The crude mixture was purified on silica (0-80% EtOAc in hexanes) togive compound 20 (7.87 g, 20.7 mmol) in 59% yield.

HNMR: ¹H NMR (400 MHz, Chloroform-d) δ 4.84 (s, 1H), 3.73 (s, 6H), 3.65(t, J=6.1 Hz, 6H), 2.57 (t, J=6.1 Hz, 6H), 1.35 (s, 9H).

Compound 28 (7.87 g, 20.7 mmol) was dissolved in MeOH (40 mL) andconcentrated sulfuric acid (10 mL) was added. The reaction was stirredat reflux under nitrogen for 24 hours, then neutralized with sodiumbicarbonate. Methanol was evaporated, and the residue partioned betweenwater and ethyl acetate. The ethyl acetate layer was washed with sodiumbicarbonate (1×) and brine (1×), then dried over sodium sulfate. Thecrude residue was purified on silica (10% MeOH in DCM) to give compound29 (5.50 g, 14.5 mmol) in 70% yield.

HNMR: ¹H NMR (400 MHz, Chloroform-d) δ 3.79-3.64 (m, 15H), 3.32 (s, 6H),2.56 (t, J=6.3 Hz, 6H).

CNMR: ¹³C NMR (101 MHz, cdcl₃) δ 172.03, 72.52, 66.77, 56.10, 51.62,34.80.

Compound 70 (723 mg, 1.90 mmol) was dissolved in MeCN (25 mL). HOBT (291mg, 1.90 mmol, 1 eq), Cbz-glycine (397 mg, 1.90 mmol, 1 eq), and DCC(392 mg, 1.90 mmol, 1 eq) were then added, and the reaction stirredovernight. MeCN was then evaporated, and the residue adsorbed ontosilica and purified using a gradient of 0-75% EtOAc in hexanes. Compound71 (866 mg, 1.52 mmol) was recovered in 80% yield.

¹H NMR (600 MHz, Chloroform-d) δ 7.33 (dd, J=24.9, 4.4 Hz, 5H), 6.33 (s,1H), 5.55 (s, 1H), 5.12 (s, 2H), 3.86 (d, J=5.1 Hz, 2H), 3.68 (t, J=5.5Hz, 21H), 3.49 (s, 1H), 2.53 (t, J=6.1 Hz, 6H).

¹³C NMR (151 MHz, cdcl₃) δ 172.14, 168.67, 156.32, 136.41, 128.45,128.05, 127.98, 69.04, 66.85, 66.71, 59.83, 51.69, 44.55, 34.64.

Expected: [M+H]⁺ 571.250, found 571.243

Compound 71 (100 mg, 0.175 mmol) was dissolved in dioxane (2 mL) and 2MNaOH (2 mL). The reaction was stirred for 3 hours, then acidified andextracted twice into ethyl acetate. The organic fraction was washed with1M HCl, then dried over sodium sulfate and evaporated to give compound72, which was used in further steps without purification.

Example 2-5. GaINAc Trivalent (FIG. 17)

Compound 72 (372 mg, 0.704 mmol, 1 eq) was dissolved in DMF (40 mL) andDIPEA (981 uL, 728 mg, 5.632 mmol, 8 eq). HBTU (1.01 g, 2.67 mmol, 3.8eq) was then added, and the reaction stirred for 10 minutes at roomtemperature before the addition of compound 68 (1.28 g, 2.67 mmol, 3.8eq). The reaction was stirred for two hours, then diluted into DCM andwashed with H3PO4 (1M, 1×), NaHCO3 (1M, 1×), and brine (1×). The organiclayer was dried over sodium sulfate and evaporated onto silica. Theresidue was purified (0-20% MeOH in DCM) to give compound 73 (831 mg,0.436 mmol) in 62% yield.

¹H NMR (500 MHz, DMSO-d₆) δ 7.91 (t, J=5.7 Hz, 3H), 7.80 (d, J=9.2 Hz,3H), 7.39-7.28 (m, 6H), 7.12 (s, 1H), 5.21 (d, J=3.4 Hz, 3H), 5.02 (s,2H), 4.97 (dd, J=11.2, 3.4 Hz, 3H), 4.55 (d, J=8.5 Hz, 3H), 4.10-3.99(m, 9H), 3.92-3.84 (m, 3H), 3.81-3.75 (m, 3H), 3.62-3.46 (m, 35H), 3.39(t, J=6.1 Hz, 6H), 3.23-3.16 (m, 6H), 2.30 (t, J=6.4 Hz, 6H), 2.10 (s,9H), 1.99 (s, 9H), 1.89 (s, 9H), 1.77 (s, 9H).

¹³C NMR (126 MHz, dmso) δ 170.40, 170.16, 170.09, 169.79, 169.48,169.04, 156.60, 137.23, 128.50, 127.94, 127.84, 101.12, 72.50, 70.65,70.07, 69.93, 69.86, 69.77, 69.59, 69.29, 68.50, 67.51, 66.89, 65.59,61.63, 60.38, 59.84, 49.50, 43.77, 38.68, 36.01, 22.95, 20.68, 20.62,20.60.

Compound 73 (710 mg, 0.372 mmol) was dissolved in dry methanol (90 mL)and cooled to 0° under nitrogen. Pd/C (71.0 mg, 10% w/w) was then added,and the reaction stirred under hydrogen (1 atm) at 0° for 16 hours. Uponcompletion, the reaction was filtered through celite and methanolevaporated to give compound 74 (657 mg, 0.370 mmol) in 99.5% yield,which was used without further purification.

Compound 74 (441 mg, 0.248 mmol) was dissolved in methanol (15 mL) andcooled to 0°. Sodium methoxide solution (400 uL, 5.4M in MeOH) was thenadded, and the reaction stirred for 30 minutes. Dowex 50WX8 was thenadded until the solution was weakly acidic. The resin was filtered offand washed thoroughly with methanol. The combined methanol fractionswere evaporated under reduced pressure to give compound 75 (274 mg,0.196 mmol) in 79% yield. Compound 75 was used in further steps withoutpurification.

Example 2-6. MIF-GN3 (FIG. 18)

Compound 34 (23.5 mg, 0.0575 mmol, 1.1 eq) and HATU (20.0 mg, 0.0522mmol, 1 eq) were dissolved in dry DMF (5 mL) and DIPEA (23.3 uL, 16.9mg, 0.131 mmol, 2.5 eq) and stirred for 10 minutes at room temperature.Compound 75 (73.0 mg, 0.0522 mmol) was then added, and the reactionstirred for 30 minutes. The mixture was loaded directly onto HPLC andpurified (20-30% MeCN in water, 3% TFA) to give compound 76 (12 mg,0.0067 mmol) in 12.8% yield.

Expected [M+H]⁺ 1787.801, found 1787.823

Example 2-7. Bicyclic ASGPR Spacer (FIG. 19)

Tetraethylene glycol (50.0 g, 258 mmol) was dissolved in THF (1 mL),cooled to 0°, and stirred. NaOH (1.65 g, 41.3 mmol, 1.6 eq) in water (1mL) was then added, followed by the dropwise addition ofp-toluenesulfonyl chloride (4.92 g, 25.8 mmol, 1 eq) in THE (3 mL). Thereaction mixture was stirred at 0° for 4 hours, then diluted into DCM.The organic layer was washed with ice-cold water (2×), brine (1×), anddried over sodium sulfate to give compound 16 (8.84 g, 25.4 mmol, 99%yield), which was used in further steps without purification.

Compound 16 (8.84 g, 25.4 mmol) was dissolved in 100% ethanol (200 mL)and sodium azide (4.128 g, 63.5 mmol, 2.5 eq) was added. The reactionwas heated to reflux for 16 hours, then cooled to room temperaturebefore the addition of water (150 mL). Ethanol was then evaporated underreduced pressure and the product extracted into ethyl acetate (2×). Theorganic layer was washed with water (1×) and brine (1×), dried oversodium sulfate, and evaporated to give compound 17 (4.82 g, 22.1 mmol)as a yellow oil in 87% yield.

HNMR: ¹H NMR (400 MHz, Chloroform-d) δ 3.69-3.64 (m, 2H), 3.61 (m, J=4.2Hz, 10H), 3.57-3.51 (m, 2H), 3.33 (td, J=5.0, 2.3 Hz, 2H), 2.81 (s, 1H).

CNMR: ¹³C NMR (101 MHz, cdcl₃) δ 72.47, 70.65, 70.63, 70.59, 70.52,70.28, 69.99, 61.60, 50.59.

Compound 17 (5.00 g, 22.8 mmol) was dissolved in pyridine (50 mL).Methanesulfonyl chloride (3.14 g, 27.4 mmol, 1.2 eq) was then added andthe reaction stirred for six hours under nitrogen. The mixture was thendiluted into ethyl acetate, washed with water (3×), 0.5M HCl (2×),saturated sodium bicarbonate (1×), and brine (1×), dried over sodiumsulfate, and evaporated to give compound 18 (5.71 g, 19.2 mmol) in 84%yield.

HNMR: ¹H NMR (400 MHz, Chloroform-d) δ 4.41-4.33 (m, 2H), 3.81-3.72 (m,2H), 3.70-3.59 (m, 10H), 3.38 (t, J=5.0 Hz, 2H), 3.06 (s, 3H).

CNMR: ¹³C NMR (101 MHz, cdcl₃) δ 70.79, 70.75, 70.71, 70.15, 69.39,69.11, 50.77, 37.78.

HRMS: Expected 298.107, found 298.105

Example 2-8. Bicyclic ASGPR Precursor (FIG. 20)

Pentaacetyl galactose (25.0 g, 64.0 mmol) was dissolved in 33% HBr inHOAc (30 mL) and stirred under nitrogen for 2 hours. The reaction wasdiluted into EtOAc (500 mL) and washed with water (3×), saturated sodiumbicarbonate (1×), and brine (1×). The organic layer was dried oversodium sulfate and evaporated to give compound 1 as a pale yellow oil inquantitative yield. The compound was used without further purification.

Compound 1 (26.34 g, 64.06 mmol) was dissolved in acetic acid (510 mL)and zinc (67.01 g, 1024 mmol) added. The mixture was stirred vigorously.A solution of CuSO4 (2.96 g, 18.6 mmol) in aqueous NaH2PO4 (128 mL,0.1M, 1.53 g) was then added, and the reaction stirred for 1 hour. Thereaction mixture was filtered over celite and the resulting water/AcOHmixture evaporated to give a white solid. The white solid was dissolvedin EtOAc (2×, 300 mL each), water (300 mL), and EtOAc (1×, 300 mL). Thelayers were separated and the organic layer further washed with water(2×), saturated sodium bicarbonate (2×), and brine (1×). The organicsolution was dried over sodium sulfate, evaporated, and purified onsilica (15-25% EtOAc in Hexanes) to give compound 2 in 84% yield (14.64g, 53.76 mmol).

¹H NMR (400 MHz, Chloroform-d) δ 6.46 (dd, J=6.3, 1.8 Hz, 1H), 5.54 (qd,J=2.8, 1.2 Hz, 1H), 5.41 (dt, J=4.7, 1.7 Hz, 1H), 4.71 (ddd, J=6.3, 2.7,1.5 Hz, 1H), 4.33 (ddt, J=7.0, 5.6, 1.4 Hz, 1H), 4.29-4.15 (m, 2H), 2.11(s, 3H), 2.06 (s, 3H), 2.00 (s, 3H).

¹³C NMR (101 MHz, Chloroform-d) δ 170.33, 170.06, 169.97, 145.30, 98.80,72.69, 63.82, 63.59, 61.85, 20.66, 20.64, 20.58.

HRMS: [M+Na]⁺ Expected 295.079, found 295.078

Procedure: Compound 2 (12.0 g, 44 mmol) was dissolved in acetonitrile(250 mL) and cooled to −10°. In a separate nitrogen-flushed flask at−10°, NaN₃ (4.3 g, 66 mmol) and ceric ammonium nitrate (87.0 g, 158mmol) were mixed and stirred vigorously. The solution of compound 2 inacetonitrile was added dropwise via cannula, and the mixture allowed toslowly reach room temperature. The reaction mixture was allowed to stirfor a total of 12 hours before dilution with ethyl acetate (500 mL) andwashing with water (3×) and brine (1×). The organic layer was dried oversodium sulfate, evaporated, and purified on silica (20-50% EtOAc inHexanes) to give compound 3 in 79% yield (13.1 g, 34.9 mmol).

¹H NMR (400 MHz, Chloroform-d) δ 6.31 (d, J=4.1 Hz, 1H), 5.60 (d, J=8.8Hz, 1H), 5.43 (dd, J=3.4, 1.3 Hz, 1H), 5.32 (t, J=3.3 Hz, 1H), 5.16 (dt,J=11.6, 3.4 Hz, 1H), 4.96 (dd, J=10.6, 3.3 Hz, 1H), 4.39-4.28 (m, 1H),4.14-4.00 (m, 5H), 3.76 (ddd, J=13.5, 9.6, 4.7 Hz, 1H), 2.19-2.05 (m,6H), 2.05-1.88 (m, 12H).

¹³C NMR (101 MHz, cdcl₃) δ 170.15-169.06, 97.91, 97.79, 96.91, 71.68,71.45, 69.35, 68.42, 66.98, 66.53, 65.85, 64.75, 61.07, 60.84, 57.38,55.82, 55.08, 20.31-20.20.

HRMS: [M+Na]⁺ expected 399.076, found 399.073

Sodium methoxide solution was prepared from ice-cold dry methanol (50mL) and sodium hydride (2.296 g, 95.67 mmol) 3 eq) and added to asolution of compound 3 (12.00 g, 31.89 mmol) in dry methanol (100 mL).After thirty minutes of stirring, the reaction was confirmed neutralizedby the addition of acetic acid and directly loaded onto silica gel. Thereaction mixture was purified over a gradient of 0-20% MeOH in DCM togive compound 4 (6.64 g, 30.3 mmol) in 95% yield.

CNMR: ¹³C NMR (101 MHz, cd₃od) δ 102.60, 100.87, 98.59, 75.65, 74.62,71.43, 70.41, 68.82, 67.81, 67.69, 67.47, 67.37, 63.73, 62.96, 60.75,60.43, 59.54, 55.42, 53.69, 45.94.

HRMS: [M+Na]⁺ expected 242.075, found 242.072

Compound 4 (5.00 g, 22.8 mmol) was dissolved in pyridine (100 mL) andstirred under nitrogen. Trimetylsilylchloride (10.43 mL, 8.929 g, 82.18mmol, 3.6 eq) was added dropwise and the mixture stirred for 6 hours.The reaction was diluted into ethyl acetate and washed with water (2×)and brine (1×). The organic layer was dried over sodium sulfate andevaporated to give the tri-TMS intermediate. Residual pyridine wasremoved by coevaporating with toluene (3×). The intermediate was takenup into dry MeOH (45 mL) and cooled to 0° before potassium carbonate (40mg) was added. The reaction was closely monitored over 1.5 hours andquenched with acetic acid (17 uL) once TLC showed complete consumptionof starting material. The product was then dry loaded onto silica andpurified with a gradient of 0-50% EtOAc in hexane to give compound 5(6.55 g, 18.0 mmol) in 79% yield.

¹³C NMR (101 MHz, cdcl₃) δ 103.36, 75.29, 73.71, 72.37, 71.41, 70.94,70.38, 64.04, 62.49, 62.15, 61.05, 60.36, 57.15, 55.17, 34.60, 31.52,25.21, 22.59, 20.93, 14.11, 14.05, 0.85, 0.57, 0.55, 0.52, 0.22, 0.14,0.01, −0.07.

HRMS: [M+Na]⁺ 386.154, found 386.156

Compound 5 (7.00 g, 19.3 mmol) was dissolved in DCM (100 mL) and stirredunder nitrogen. Dess-Martin periodane (9.82 g, 23.2 mmol, 1.2 eq) wasadded and the mixture stirred for 2 hours. The reaction was diluted intoDCM and washed with water (2×) and brine (1×). The organic layer wasdried over sodium sulfate and evaporated to give the intermediatealdehyde.

Compound 6 was dissolved in molecular sieve-dried EtOH (100 mL).Paraformaldehyde (36.50 g, 384.9 mmol, 20 eq) and 21% sodium ethoxidesolution (14.5 mL, 38.5 mmol, 2 eq) were added and the reaction stirredfor 8 hours. The solvent was evaporated and the product adsorbed ontosilica. The product was purified using a gradient of 0-25% MeOH in DCMto afford compound 7 (2.981 g, 11.97 mmol) in 62% yield.

HRMS: [M+Na]⁺ expected 272.086 (+Na), found 272.083

L6-7 (500 mg, 2.00 mmol) was dissolved in water (4.5 mL) and sulfuricacid (0.5 mL). The reaction was sealed in a microwave vial and heated at100° for 40 minutes. The reaction was cooled to 0°, then diluted withMeOH (10 mL) and neutralized by the addition of concentrated ammoniasolution. Salts were filtered off and washed several times withmethanol. The filtrate was adsorbed onto silica and purified on agradient of 0-15% MeOH in DCM to give compound L6-8 (347 mg, 1.60 mmol)in 80% yield.

¹³C NMR (101 MHz, cd₃od) δ 102.70, 85.32, 71.03, 69.59, 69.49, 66.07,61.85

Example 2-9. Bicyclic ASGPR Ligand CF3 (FIG. 21)

Compound (400 mg, 1.84 mmol) was dissolved in methanol (30 mL) and thereaction flask purged with nitrogen. Lindlar's catalyst (40.0 mg, 10 wt%) was then added, and the reaction mixture stirred under a 1 atmhydrogen atmosphere (balloon) for 6 hours. The reaction was filteredover celite and evaporated to give compound 10 (351 mg, 1.84 mmol) inquantitative yield, which was used in the next reaction without furtherpurification.

Compound (351 mg, 1.84 mmol) was dissolved in pyridine (15 mL) andtreated with trifluoroacetic anhydride (1.24 mL, 1.85 g, 8.83 mmol, 4.8eq). The reaction was stirred for 6 hours, then diluted into ethylacetate and washed with 1M HCl (1×), saturated sodium bicarbonate (1×),and brine (1×). The organic layer was dried over sodium sulfate andevaporated to give compound 11 (1.01 g, 1.75 mmol) in 95% yield, whichwas used in further steps without purification.

Compound 11 (1.01 g, 1.75 mmol) was dissolved in methanol (25 mL) anddry sodium methoxide (86.2 mg, 1.60 mmol, 4 eq) was added. The reactionwas stirred for one hour at room temperature, then neutralized withacetic acid and evaporated onto silica. The crude mixture was purifiedon silica (0-15% MeOH in DCM) to give compound 12 (482 mg, 1.68 mmol) in96% yield.

¹H NMR (400 MHz, DMSO-d₆) δ 9.51 (d, J=6.6 Hz, 1H), 5.15 (s, 1H),4.98-4.90 (m, 1H), 4.87 (d, J=5.6 Hz, 1H), 4.75-4.70 (m, 1H), 3.86-3.80(m, 2H), 3.80-3.70 (m, 2H), 3.67-3.54 (m, 3H).

¹³C NMR (101 MHz, dmso) δ 157.47, 157.11, 117.74, 114.87, 100.28, 84.21,68.77, 68.28, 66.00, 60.51, 55.95, 40.56, 40.35, 40.15, 39.94, 39.73,39.52, 39.31.

HRMS: [M+H]⁺ Expected 288.069, found 288.064

Compound 12 (110 mg, 0.383 mmol) was dissolved in DMF (8 mL) anddimethoxypropane (236 uL, 200 mg, 1.92 mmol, 5 eq) and camphorsulfonicacid (45 mg, 0.192 mmol, 0.5 eq) were added. The reaction was stirred at700 overnight, then DMF evaporated under reduced pressure. The residuewas dissolved in ethyl acetate, washed with saturated sodium bicarbonate(1×) and brine (1×), then evaporated onto silica and purified (0-5% MeOHin DCM) to give compound 13 (99.1 mg, 0.303 mmol) in 79% yield.

HNMR: ¹H NMR (400 MHz, Chloroform-d) δ 6.87 (d, J=9.0 Hz, 1H), 5.35 (d,J=2.1 Hz, 1H), 4.18-4.11 (m, 2H), 4.11-4.03 (m, 2H), 3.84 (t, J=8.2 Hz,2H), 3.74 (d, J=7.9 Hz, 1H), 2.66 (d, J=6.6 Hz, 1H), 1.52 (s, 3H), 1.32(s, 3H).

CNMR: ¹³C NMR (101 MHz, cdcl₃) δ 157.87, 157.50, 157.12, 156.75, 119.93,117.07, 114.21, 112.04, 111.35, 100.22, 81.55, 75.57, 75.00, 68.44,60.96, 55.16, 27.67, 26.16.

HRMS: [M+H]⁺ Expected 328.101, found 328.095

Compound 13 (99.1 mg, 0.303 mmol) was dissolved in DMF (5 mL) andtreated with sodium hydride (8.7 mg, 0.364 mmol, 1.2 eq), then stirredunder nitrogen for 15 minutes. Compound 18 (108 mg, 0.364 mmol, 1.2 eq)was then added, and the reaction stirred for 1 hour. The reaction wasneutralized by the dropwise addition of acetic acid. The solvent wasremoved under reduced pressure and the residue taken up into ethylacetate and washed with brine (4×), and the organic layer was dried oversodium sulfate and evaporated onto silica. The crude mixture waspurified on silica (50-100% EtOAc in hexanes) to give compound 14 (131mg, 0.248 mmol) in 82% yield.

HNMR: ¹H NMR (400 MHz, DMSO-d₆) δ 9.75 (d, J=8.3 Hz, 1H), 5.29 (s, 1H),4.40 (t, J=6.7 Hz, 1H), 4.30 (d, J=5.9 Hz, 1H), 3.88-3.66 (m, 5H),3.64-3.48 (m, 14H), 3.39 (t, J=5.0 Hz, 2H), 1.41 (s, 3H), 1.28 (s, 3H).

Compound 14 (131 mg, 0.240 mmol) was dissolved in methanol (10 mL) andstirred under a nitrogen atmosphere. Lindlar catalyst (13.1 mg, 10 wt %)was then added, and the reaction stirred for 6 hours under H₂ atmosphere(1 atm). The reaction was then filtered over celite and the solventevaporated to give compound 15 (120 mg, 0.240 mmol) in quantitativeyield, which was used without further purification.

HRMS: [M+H]⁺ Expected 503.222, found 503.223

Example 2-10. MIF Binding Divalent (FIG. 23)

Serinol (2.00 g, 22.0 mmol) was dissolved in dichloromethane (40 mL) andtrimethylamine (10 mL). Di-tert-butyl dicarbonate (5.76 g, 26.4 mmol,1.2 eq) was then added, and the reaction stirred for 4 hours. Themixture was evaporated and the residue portioned between ethyl acetateand water. The organic fraction was washed with water (1×), 1M HCl (2×),saturated sodium bicarbonate (1×), and brine (1×) before drying oversodium sulfate and evaporation to give compound 23 (3.99 g, 20.9 mmol)in 95% yield, which was used without purification in further steps.

Compound 23 (3.99 g, 20.9 mmol) was dissolved in a mixture of dioxane(12 mL) and aqueous KOH (1.63 g, 29 mmol, 2.4 mL). Acrylonitrilte (3.02mL, 2.44 g, 46.0 mmol, 2.2 eq) was then added dropwise over a period of2.5 hours, and the reaction stirred under nitrogen for 24 hours. Thereaction was neutralized with the addition of 2M HCl (16 mL) andportioned between DCM and water. The organic layer was washed with water(2×) and brine (1×), dried over sodium sulfate, and evaporated. Thecrude mixture was purified on silica (20-100% EtOAc in hexanes) to givecompound 20 (4.96 g, 16.7 mmol) in 80% yield.

HNMR: ¹H NMR (400 MHz, Chloroform-d) δ 4.91 (d, J=8.9 Hz, 1H), 3.94-3.81(m, 1H), 3.68 (t, J=6.1 Hz, 4H), 3.65-3.48 (m, 4H), 2.60 (t, J=6.1 Hz,4H), 1.42 (s, 9H).

CNMR: ¹³C NMR (101 MHz, cdcl₃) δ 171.11, 155.31, 117.88, 79.70, 69.12,65.53, 49.24, 28.30, 18.83, 14.16.

Compound 24 (4.96 g, 16.7 mmol) was dissolved in methanol (40 mL) andconcentrated sulfuric acid (10 mL) was added. The mixture was heated atreflux for 24 hours under a nitrogen atmosphere, then cooled to roomtemperature. Excess sodium bicarbonate was then added, followed bydi-tert-butyl dicarbonate (4.37 g, 20.04 mmol, 1.2 eq), and the reactionstirred at room temperature for 6 hours. The cloudy mixture wasportioned between water and ethyl acetate, and the organic fractionwashed with water (1×), 0.5M HCl (2×), saturated sodium bicarbonate(1×), and brine (1×), dried over sodium sulfate, and evaporated.Compound 20 was purified over a gradient of 0-10% MeOH in DCM on silica,and recovered in 74% yield (4.50 g, 12.4 mmol).

HNMR: ¹H NMR (400 MHz, Chloroform-d) δ 4.90 (d, J=8.6 Hz, 1H), 3.82 (brs, 1H), 3.70-3.59 (m, 10H), 3.51-3.34 (m, 4H), 2.51 (t, J=6.3 Hz, 4H),1.38 (s, 9H).

CNMR: ¹³C NMR (101 MHz, cdcl₃) δ 171.86, 155.34, 79.20, 69.19, 66.41,51.58, 49.29, 34.75, 28.28.

Compound 25 (1.00 g, 2.75 mmol) was dissolved in dry MeOH (10 mL) andTFA (1 mL) and stirred for 15 minutes. Volatiles were evaporated underreduced pressure to give compound 26 as the TFA salt (1.04 g) inquantitative yield.

Compound 34 (50.0 mg, 0.123 mmol) was dissolved in DMF (5 mL) and DIPEA(214 uL, 159 mg, 1.23 mmol, 10 eq) and stirred under nitrogen. HBTU(102.4 mg, 0.270 mmol, 2.2 eq) was then added, and the reaction stirredfor 15 minutes. Compound 26 (102 mg, 0.270 mmol, 2.2 eq) dissolved inDMF (1 mL) was then added dropwise, and the reaction stirred for 1 hour.The mixture was diluted into ethyl acetate, and washed with 1M HCl (2×)and brine (5×). The organic layer was evaporated to give a gummyresidue, which was purified on reverse phase HPLC (35-45% MeCN in water,0.1% TFA) to give compound 40 (62.6 mg, 0.0959 mmol) in 78% yield.

HRMS: expected 654.258, found 654.259

Compound 40 (62.6 mg, 0.0959 mmol) was dissolved in dioxane (1.8 mL) and1M NaOH (0.2 mL) was added. The solution was stirred at room temperaturefor 2 hours, then acidified (pH 3) and evaporated. The residue wasresuspended in EtOAc, washed with 1M HCl, and dried over sodium sulfate.The organic layer was evaporated to give compound 41 as an oil (57.6 mg,0.0921 mmol) in 96% yield, which was used without further purification.

Example 2-11. MIF Binding Trivalent (FIG. 23)

Compound 34 (50.0 mg, 0.123 mmol) was dissolved in DMF (5 mL) and DIPEA(214 uL, 159 mg, 1.23 mmol, 10 eq) and stirred under nitrogen. HBTU (154mg, 0.405 mmol, 3.3 eq) was then added, and the reaction stirred for 15minutes. Compound 29 (200 mg, 0.405 mmol, 3.3 eq) dissolved in DMF (1mL) was then added dropwise, and the reaction stirred for 1 hour. Themixture was diluted into ethyl acetate, and washed with 1M HCl (2×) andbrine (5×). The organic layer was evaporated to give a gummy residue,which was purified on reverse phase HPLC (35-50% MeCN in water, 0.1%TFA) to give compound 44 (79.3 mg, 0.103 mmol) in 84% yield.

HRMS: [M+H]⁺ expected 770.305, found 770.308

Compound 44 (79.3 mg, 0.103 mmol) was dissolved in dioxane (1.8 mL) and1M NaOH (0.2 mL) was added. The solution was stirred at room temperaturefor 2 hours, then acidified (pH 3) and evaporated. The residue wasresuspended in EtOAc, washed with 1M HCl, and dried over sodium sulfate.The organic layer was evaporated to give compound 41 as an oil (68.9 mg,0.0948 mmol) in 92% yield, which was used without further purification.

Example 2-12. MIF-AcF3-2 (FIG. 24)

Compound 41 (57.6 mg, 0.0921 mmol) was dissolved in DMF (1.8 mL) andDIPEA (0.2 mL). HBTU (84.0 mg, 0.222 mmol, 2.4 eq) was then added, andthe reaction stirred for 15 minutes before the addition of compound 15(111 mg, 0.222 mmol, 2.4 eq). The reaction was stirred for 1 hour, thenevaporated to give a red residue which was used in the next reactionwithout purification.

Compound 42 (crude, 0.0921 mmol scale) was dissolved in 1M HCl (1 mL)and stirred for 2 hours. The reaction was purified directly by HPLC(20-40% MeCN in H₂O, +3% TFA) to give compound 43 (44.66 mg, 0.0295mmol) in 32% yield.

Expected (H) 1514.570, found 1514.561

Example 2-13. MIF-AcF3-3 (FIG. 25)

Compound 45 (68.9 mg, 0.0948 mmol) was dissolved in DMF (1.8 mL) andDIPEA (0.2 mL). HBTU (126 mg, 0.333 mmol, 3.6 eq) was then added, andthe reaction stirred for 15 minutes before the addition of compound 15(167 mg, 0.333 mmol, 3.6 eq). The reaction was stirred for 1 hour, thenevaporated to give a reddish residue which was used in the next reactionwithout purification.

Compound 38 (crude, 0.0948 mmol scale) was dissolved in 1M HCl (1 mL)and stirred for 2 hours. The reaction was purified directly by HPLC(20-40% MeCN in H₂O, +3% TFA) to give compound 39 (78.1 mg, 0.0379 mmol)in 40% yield.

Expected (2H, /2) 1030.891 Found 1030.903

Example 2-14. Synthesis of MIF-AcF2-3, MIF-Ac-3, MIF-Et-3

Set forth in FIGS. 26-29 are the chemical syntheses of MIF-AcF2-3,MIF-Ac-3, MIF-Et-3 and MIF-EtF3-3 produced using analogous methods tothose presented above with minor variation.

The foregoing outlines features of several embodiments so that thoseskilled in the art may better understand the aspects of the presentdisclosure. Those skilled in the art should appreciate that they mayreadily use the present disclosure as a basis for designing or modifyingother processes and structures for carrying out the same purposes and/orachieving the same advantages of the embodiments introduced herein.Those skilled in the art should also realize that such equivalentconstructions do not depart from the spirit and scope of the presentdisclosure, and that they may make various changes, substitutions, andalterations herein without departing from the spirit and scope of thepresent disclosure.

1. A bifunctional compound according to the chemical structure:

wherein: [MIFBM/IgGBM] is a MIF or IgG Binding Moiety which bindsrespectively to circulating MIF or IgG in a subject, each of which isrelated to a disease state or condition and is to be removed by actionof hepatocytes or other cells of the subject; [ASGPRBM] is a BindingMoiety which binds to asialoglycoprotein receptors on hepatocytes orother cell receptors in a subject; each [CON] is an optional connectorchemical moiety which, when present, connects the [LINKER] to [ASGPRBM]or to [MIFBM/IgGBM]; [LINKER] is a chemical moiety having a valency from1 to 15, which covalently attaches to one or more [ASGPRBM] or[MIFBM/IgGBM] groups, optionally through a [CON], wherein the [LINKER]optionally itself contains one or more [CON] groups; k′ is 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; j′ is 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15; h and h′ are each independently 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; i_(L) is 0, 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; with the proviso that at leastone of h, h′, and i_(L) is at least 1, or a salt, stereoisomer, orsolvate thereof.
 2. The compound of claim 1, wherein k′, j′, h, h′, andi_(L) are each independently 1, 2, or
 3. 3. The compound of claim 1,wherein [MIFMB] is a group according to the chemical structure:

wherein: X_(M) is —(CH₂)_(IM)—, —O—(CH₂)_(IM)—, —S—(CH₂)_(IM)—,—NR_(M)—(CH₂)_(IM)—, —C(O)—(CH₂)_(IM)—, a PEG group containing from 1 to8 ethylene glycol residues, or —C(O)(CH₂)_(IM)NR_(M)—; R_(M) is H orC₁-C₃ alkyl optionally substituted with one or two hydroxyl groups; IMis 0, 1, 2, 3, 4, 5, or 6; or wherein [IgGMB] is a group according tothe chemical structure:

wherein DNP is 2,4-dinitrophenyl; or wherein [IgGMB] is a groupaccording to the chemical structure:

wherein: Y′ is H or NO₂; X is O, CH₂, NR¹, S(O), S(O)₂, —S(O)₂O,—OS(O)₂, or OS(O)₂O; and R¹ is H, C₁-C₃ alkyl, or —C(O)(C₁-C₃ alkyl); orwherein [IgGMB] is a group according to the chemical structure:

wherein R¹ is the same as above; and K″ is 1, 2, 3, 4, or 5, or wherein[IgGMB] is a group according to the chemical structure:

wherein: X′ is CH₂, O, N—R¹′, or S; R^(1′) is H or C₁-C₃ alkyl; and Z isa bond, a monosaccharide, disaccharide, or oligosaccharide; or wherein[IgGBM] is a group according to the chemical structure:

wherein: X_(R) is O, S, or NR¹; X_(M) is O, NR¹, or S, and R¹ is H orC₁-C₃ alkyl; or wherein [IgGBM] is a group according to the chemicalstructure:

wherein: X″ is O, CH₂, NR¹, or S; and R¹ is H, C₁-C₃ alkyl, or—C(O)(C₁-C₃ alkyl); or

wherein: X^(b) is a bond, O, CH₂, NR¹, or S; and R¹ is the same asabove; or wherein [IgGBM] is a group according to the chemicalstructure:

wherein R^(N02) is a dinitrophenyl group optionally linked through CH₂,S(O), S(O)₂, —S(O)₂O, —OS(O)₂, or OS(O)₂O; or wherein [IgGBM] is adinitrophenyl group according to the chemical structure:

wherein: X is O, CH₂, NR¹, S(O), S(O)₂, —S(O)₂O, —OS(O)₂, or OS(O)₂O;and R¹ is H, C₁-C₃ alkyl, or —C(O)(C₁-C₃ alkyl), or wherein [IgGBM] is a3-indoleacetic acid group according to the chemical structure:

wherein K′″ is 1, 2, 3, or 4, or wherein [IgGBM] is a group according toa chemical structure selected from the group consisting of:

which is covalently attached to a [CON] group, a [LINKER] group, or an[ASGPRBM] group, through an amine group optionally substituted withC₁-C₃ alkyl; or wherein [IgGBM] is a peptide selected from the groupconsisting of: PAM; D-PAM; D-PAM-Φ; (SEQ ID NO: 1) TWKTSRISIF;(SEQ ID NO: 2) FGRLVSSIRY;

Fc-III; FcBP-1; FcBP-2; Fc-III-4c; (SEQ ID NO: 3) EPIHRSTLTALL;(SEQ ID NO: 4) APAR;

FcRM; (SEQ ID NO: 5) HWRGWV; (SEQ ID NO: 6) HYFKFD; (SEQ ID NO: 7)HFRRHL; (SEQ ID NO: 8) HWCitGWV;

D2AAG; DAAG; (SEQ ID NO: 9-Lact-E) cyclo[(N-Ac)S(A)-RWHYFK-Lact-E];(SEQ ID NO:10-Lact-E) cyclo[(N-Ac)-Dap(A)-RWHYFK-Lact-E];(SEQ ID NO: 11) cyclo[Link-M-WFRHYK]; (SEQ ID NO: 12) NKFRGKYK;(SEQ ID NO: 13) NARKFYKG; (SEQ ID NO: 14) FYWHCLDE; (SEQ ID NO: 15)FYCHWALE; (SEQ ID NO: 16) FYCHTIDE; (SEQ ID NO: 17) RRGW;(SEQ ID NO: 18) KHRFNKD;

or wherein [ASGPRBM] is a group according to the chemical structure:

wherein X is 1-4 atoms in length and comprises O, S, N(R^(N1)) orC(R^(N1))(R^(N1)) groups, such that: when X is 1 atom in length, X is O,S, N(R^(N1)), or C(R^(N1))(R^(N1)), when X is 2 atoms in length, no morethan 1 atom of X is O, S, or N(R^(N1)), when X is 3 or 4 atoms inlength, no more than 2 atoms of X are O, S, or N(R^(N1)); wherein R^(N1)is H or C₁-C₃ alkyl optionally substituted with 1-3 halo groups; whereinR₁ and R₃ are each independently H, —(CH₂)_(K)OH, —(CH₂)_(K)O(C₁-C₄alkyl) optionally substituted with 1-3 halo groups, C₁-C₄ alkyloptionally substituted with 1-3 halo groups, —(CH₂)_(K)vinyl,—O—(CH₂)_(K)vinyl, —(CH₂)_(K)alkynyl, —(CH₂)_(K)COOH,—(CH₂)_(K)C(O)O—(C₁-C₄ alkyl) optionally substituted with 1-3 halogroups, O—C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3 halogroups, —C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3 halo groups,or R₁ and R₃ are each independently

 which is optionally substituted with up to three halo groups; C₁-C₄alkyl, each of which alkyl group is optionally substituted with from oneto three halo groups or one or two hydroxyl groups; or O—(C₁-C₄ alkyl),each of which alkyl groups is optionally substituted with from one tothree halo groups or one or two hydroxyl groups; R₁ and R₃ are eachindependently a group according to the chemical structure:

 wherein R⁷ is O—(C₁-C₄ alkyl) optionally substituted with 1 to 3 halogroups or 1-2 hydroxy groups, —NR^(N3)R^(N4), or

 or R₁ and R₃ are each independently a group according to the structure:

group, wherein CYC is a ring selected from the group consisting of:

and C₃-C₈ saturated carbocyclic, wherein each of LINKERX, R^(C), and—(CH₂)_(K)— are attached to an open valence in CYC; wherein R^(C) isabsent, H, C₁-C₄ alkyl optionally substituted with from 1-3 halo groupsor 1-2 hydroxyl groups, or a group according to the structure:

wherein R₄, R₅ and R₆ are each independently, H, halo, CN,NR^(N1)R^(N2), —(CH₂)_(K)OH, —(CH₂)_(K)O(C₁-C₄ alkyl) optionallysubstituted with 1-3 halo groups, C₁-C₃ alkyl optionally substitutedwith 1-3 halo groups, —O—(C₁-C₃-alkyl) optionally substituted with 1-3halo groups, —(CH₂)_(K)COOH, —(CH₂)_(K)C(O)O—(C₁-C₄ alkyl) optionallysubstituted with 1-3 halo groups, O—C(O)—(C₁-C₄ alkyl) optionallysubstituted with 1-3 halo groups, —C(O)—(C₁-C₄ alkyl) optionallysubstituted with 1-3 halo groups, or wherein R^(C) is

wherein R^(N), R^(N1), and R^(N2) are each independently H or C₁-C₃alkyl optionally substituted with one to three halo groups or one or twohydroxyl groups; wherein K is independently 0, 1, 2, 3, or 4; wherein K′is 1, 2, 3, or 4; wherein R^(N3) is H, or C₁-C₃ alkyl optionallysubstituted with 1-3 halo groups or 1-2 hydroxy groups; wherein R^(N4)is H, C₁-C₃ alkyl optionally substituted with 1-3 halo groups or 1-2hydroxy groups, or

wherein

 is a linker group which comprises at least one [MIFBM/IgGBM] group andlinks the [MIFBM/IgGBM] group to the [ASGPRBM] through one or moreoptional [CON] groups, or is a linker group which contains at least oneor more functional groups which can be used to covalently bond thelinker group to at least one [MIFBM/IgGBM] group or optional [CON]group; wherein R₂ is

wherein R^(AM) is H, C₁-C₄ alkyl optionally substituted with up to 3halo groups and one or two hydroxyl groups, —(CH₂)_(K)COOH,—(CH₂)_(K)C(O)O—(C₁-C₄ alkyl) optionally substituted with 1-3 halogroups, —O—C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3 halogroups, —C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3 halo groups,—(CH₂)_(K)—NR^(N3)R^(N4); or R₂ is

wherein: R^(TA) is H, CN, NR^(N1)R^(N2), —(CH₂)_(K)OH, —(CH₂)_(K)O(C₁-C₄alkyl) optionally substituted with 1-3 halo groups, C₁-C₄ alkyloptionally substituted with 1-3 halo groups, —(CH₂)_(K)COOH,—(CH₂)_(K)C(O)O—(C₁-C₄ alkyl) optionally substituted with 1-3 halogroups, —O—C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3 halogroups, —C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3 halo groups,or R^(TA) is C₃-C₁₀ aryl or a three- to ten-membered heteroaryl groupcontaining up to 5 heteroaryl atoms, each of the aryl or heteroarylgroups being optionally substituted with up to three CN, NR^(N1)R^(N2),—(CH₂)_(K)OH, —(CH₂)_(K)O(C₁-C₄ alkyl) optionally substituted with 1-3halo groups, C₁-C₃ alkyl optionally substituted with 1-3 halo groups or1-2 hydroxy groups, —O—(C₁-C₃-alkyl) optionally substituted from 1-3halo groups, —(CH₂)_(K)COOH, —(CH₂)_(K)C(O)O—(C₁-C₄ alkyl) optionallysubstituted with 1-3 halo groups, O—C(O)—(C₁-C₄ alkyl) optionallysubstituted with 1-3 halo groups, or —(CH₂)_(K)C(O)—(C₁-C₄ alkyl)optionally substituted with 1-3 halo groups, or R^(TA) is

 optionally substituted with up to three C₁-C₃ alkyl groups which areoptionally substituted with up to three halo groups, or R^(TA) is

wherein R^(N), R^(N1), and R^(N2) are each independently H or C₁-C₃alkyl optionally substituted with one to three halo groups or one or twohydroxyl groups and each —(CH₂)_(K) group is optionally substituted with1-4 C₁-C₃ alkyl groups which are optionally substituted with 1-3 fluorogroups or 1-2 hydroxyl groups; or a salt, stereoisomer, or solvatethereof.
 4. The compound of claim 1, wherein the [MIFMB] group is amoiety according to the chemical structure:

wherein: X_(M) is —(CH₂)_(IM)—, —O—(CH₂)_(IM)—, —S—(CH₂)_(IM)—,—NR_(M)—(CH₂)_(IM)—, —C(O)—(CH₂)_(IM)—, a PEG group containing from 1 to8 ethylene glycol residues, or —C(O)(CH₂)_(IM)NR_(M)—; R_(M) is H orC₁-C₃ alkyl optionally substituted with one or two hydroxyl groups; andIM is 0, 1, 2, 3, 4, 5, or 6, or a pharmaceutically acceptable salt orstereoisomer thereof.
 5. The compound of claim 1, wherein the [ASGPRBM]group is a group according to the chemical structure:

wherein X is 1-4 atoms in length and comprises O, S, N(R^(N1)) orC(R^(N1))(R^(N1)) groups, such that: when X is 1 atom in length, X is O,S, N(R^(N1)), or C(R^(N1))(R^(N1)), when X is 2 atoms in length, no morethan 1 atom of X is O, S, or N(R^(N1)), when X is 3 or 4 atoms inlength, no more than 2 atoms of X are O, S, or N(R^(N1)); wherein R^(N1)is H or C₁-C₃ alkyl optionally substituted with 1-3 halo groups; whereinR₁ and R₃ are each independently H, —(CH₂)_(K)OH, —(CH₂)_(K)O(C₁-C₄alkyl) optionally substituted with 1-3 halo groups, C₁-C₄ alkyloptionally substituted with 1-3 halo groups, —(CH₂)_(K)vinyl,—O—(CH₂)_(K)vinyl, —(CH₂)_(K)alkynyl, —(CH₂)_(K)C00H,—(CH₂)_(K)C(O)O—(C₁-C₄ alkyl) optionally substituted with 1-3 halogroups, O—C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3 halogroups, —C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3 halo groups,or R₁ and R₃ are each independently

 which is optionally substituted with up to three halo groups; C₁-C₄alkyl, each of which alkyl group is optionally substituted with from oneto three halo groups or one or two hydroxyl groups; or O—(C₁-C₄ alkyl),each of which alkyl groups is optionally substituted with from one tothree halo groups or one or two hydroxyl groups; R₁ and R₃ are eachindependently a group according to the chemical structure:

 wherein R⁷ is O—(C₁-C₄ alkyl) optionally substituted with 1 to 3 halogroups or 1-2 hydroxy groups, —NR^(N3)R^(N4), or

 or R₁ and R₃ are each independently a group according to the structure:

 group wherein CYC is a ring selected from the group consisting of:

and C₃-C₈ saturated carbocyclic, wherein each of LINKERX, R^(C), and—(CH₂)_(K)— are attached to an open valence in CYC; wherein R^(C) isabsent, H, C₁-C₄ alkyl optionally substituted with from 1-3 halo groupsor 1-2 hydroxyl groups, or a group according to the structure:

wherein R₄, R₅ and R₆ are each independently, H, halo, CN,NR^(N1)R^(N2), —(CH₂)_(K)OH, —(CH₂)_(K)O(C₁-C₄ alkyl) optionallysubstituted with 1-3 halo groups, C₁-C₃ alkyl optionally substitutedwith 1-3 halo groups, —O—(C₁-C₃-alkyl) optionally substituted with 1-3halo groups, —(CH₂)_(K)COOH, —(CH₂)_(K)C(O)O—(C₁-C₄ alkyl) optionallysubstituted with 1-3 halo groups, O—C(O)—(C₁-C₄ alkyl) optionallysubstituted with 1-3 halo groups, —C(O)—(C₁-C₄ alkyl) optionallysubstituted with 1-3 halo groups, or wherein R^(C) is

wherein R^(N), R^(N1), and R^(N2) are each independently H or C₁-C₃alkyl optionally substituted with one to three halo groups or one or twohydroxyl groups; wherein K is independently 0, 1, 2, 3, or 4; wherein K′is 0, 1, 2, 3, or 4; wherein R^(N3) is H, or C₁-C₃ alkyl optionallysubstituted with 1-3 halo groups or 1-2 hydroxy groups; wherein R^(N4)is H, C₁-C₃ alkyl optionally substituted with 1-3 halo groups or 1-2hydroxy groups, or

wherein

 is a linker group which comprises at least one [MIFBM/IgGBM] group andlinks the [MIFBM/IgGBM] group to the [ASGPRBM] through one or moreoptional [CON] groups, or is a linker group which contains at least oneor more functional groups which can be used to covalently bond thelinker group to at least one [MIFBM/IgGBM] group or optional [CON]group; wherein R₂ is

wherein R^(AM) is H, C₁-C₄ alkyl optionally substituted with up to 3halo groups and one or two hydroxyl groups, —(CH₂)_(K)COOH,—(CH₂)_(K)C(O)O—(C₁-C₄ alkyl) optionally substituted with 1-3 halogroups, —O—C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3 halogroups, —C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3 halo groups,—(CH₂)_(K)—NR^(N3)R^(N4); or R₂ is

wherein: R^(TA) is H, CN, NR^(N1)R^(N2), —(CH₂)_(K)OH, —(CH₂)_(K)O(C₁-C₄alkyl) optionally substituted with 1-3 halo groups, C₁-C₄ alkyloptionally substituted with 1-3 halo groups, —(CH₂)_(K)COOH,—(CH₂)_(K)C(O)O—(C₁-C₄ alkyl) optionally substituted with 1-3 halogroups, —O—C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3 halogroups, —C(O)—(C₁-C₄ alkyl) optionally substituted with 1-3 halo groups,or R^(TA) is a C₃-C₁₀ aryl or a three- to ten-membered heteroaryl groupcontaining up to 5 heteroaryl atoms, each of the aryl or heteroarylgroups being optionally substituted with up to three CN, NR^(N1)R^(N2),—(CH₂)_(K)OH, —(CH₂)_(K)O(C₁-C₄ alkyl) optionally substituted with 1-3halo groups, C₁-C₃ alkyl optionally substituted with 1-3 halo groups or1-2 hydroxy groups, —O—(C₁-C₃-alkyl) optionally substituted from 1-3halo groups, —(CH₂)_(K)COOH, —(CH₂)_(K)C(O)O—(C₁-C₄ alkyl) optionallysubstituted with 1-3 halo groups, O—C(O)—(C₁-C₄ alkyl) optionallysubstituted with 1-3 halo groups, or —(CH₂)_(K)C(O)—(C₁-C₄ alkyl)optionally substituted with 1-3 halo groups, or R^(TA) is

optionally substituted with up to three C₁-C₃ alkyl groups which areoptionally substituted with up to three halo groups, or R^(TA) is

wherein R^(N), R^(N1), and R^(N2) are each independently H or C₁-C₃alkyl optionally substituted with one to three halo groups or one or twohydroxyl groups and each —(CH₂)_(K) group is optionally substituted with1-4 C₁-C₃ alkyl groups which are optionally substituted with 1-3 fluorogroups or 1-2 hydroxyl groups; or a salt, stereoisomer, or solvatethereof.
 6. The compound of claim 4, wherein: X in [ASGPRBM] is—O—C(R^(N1))(R^(N1))—, —C(R^(N1))(R^(N1))—O—, —S—C(R^(N1))(R^(N1))—,—C(R^(N1))(R^(N1))—S—, —N(R^(N1))—C(R^(N1))(R^(N1))—,—C(R^(N1))(R^(N1))—N(R^(N1))—, or —C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—,when X is 2 atoms in length, X in [ASGPRBM] is—O—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—,—C(R^(N1))(R^(N1))—O—C(R^(N1))(R^(N1))—, —O—C(R^(N1))(R^(N1))—O—,—O—C(R^(N1))(R^(N1))—S—, —O—C(R^(N1))(R^(N1))—N(R^(N1))—,—S—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—,—C(R^(N1))(R^(N1))—S—C(R^(N1))(R^(N1))—,—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))S, —S—C(R^(N1))(R^(N1))—S—,—S—C(R^(N1))(R^(N1))—O—, —S—C(R^(N1))(R^(N1))—N(R^(N1))—,—N(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—,—C(R^(N1))(R^(N1))—N(R^(N1))—C(R^(N1))(R^(N1))—,—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—N(R^(N1)),—N(R^(N1))—C(R^(N1))(R^(N1))—N(R^(N1))—, or—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1)), when X is 3atoms in length, and X in [ASGPRBM] is—O—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—,—C(R^(N1))(R^(N1))—O—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—,—O—C(R^(N1))(R^(N1))—O—C(R^(N1))(R^(N1))—,—S—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—,—C(R^(N1))(R^(N1))—S—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—,—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—S—C(R^(N1))(R^(N1))—,—S—C(R^(N1))(R^(N1))—S—C(R^(N1))(R^(N1))—,—N(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))—, or—C(R^(N1))(R^(N1))—N(R^(N1))—C(R^(N1))(R^(N1))—C(R^(N1))(R^(N1))— when Xis 4 atoms in length.
 7. The compound of claim 4, wherein X is OCH₂ orCH₂O and wherein R^(N1) is H.
 8. The compound of claim 5, wherein X_(M)is a PEG group containing from 1 to 8 ethylene glycol residues, orwherein X_(M) is —C(O)—(CH₂)_(IM)— and wherein IM is 1, 2, or
 3. 9. Thecompound of claim 4, wherein the [ASGPRBM] group is a group according tothe chemical structure:

or a salt, stereoisomer, or solvate thereof.
 10. The compound of claim4, wherein the [ASGPRBM] group is a group according to the chemicalstructure:

wherein: R^(A) is C₁-C₃ alkyl optionally substituted with 1-5 halogroups; Z_(A) is —(CH₂)_(IM)—, —O—(CH₂)_(IM)—, —S—(CH₂)_(IM)—,—NR_(M)—(CH₂)_(IM)—, —C(O)—(CH₂)_(IM)—, a PEG group containing from 1 to8 ethylene glycol residues, or —C(O)(CH₂)_(IM)NR_(M)—; and Z_(B) isabsent, —(CH₂)_(IM)—, —C(O)—(CH₂)_(IM)—, or —C(O)—(CH₂)_(IM)—NR_(M)—.11. The compound of claim 12, wherein at least one applies: R^(A) is amethyl or ethyl group which is optionally substituted with 1-3 fluorogroups; Z_(A) is a PEG group containing from 1 to 4 ethylene glycolresidues.
 12. The compound of claim 4, wherein R₁ and R₃ are eachindependently a group according to the chemical structure:


13. The compound of claim 4, wherein R₁ and R₃ of the [ASGPRBM] groupare each independently a moiety selected from the group consisting of:


14. The compound of claim 4, where R₂ of the [ASGPRBM] group is a moietyselected from the group consisting of:


15. The compound of claim 4, wherein the [IgGBM] is a group according tothe chemical structure:

where K′″ is 0, 1, 2, 3, or
 4. 16. The compound of claim 4, wherein the[IgGBM] group is a peptide moiety according to the chemical structure:


17. The compound of claim 1, wherein the linker is a polyethyleneglycolcontaining linker having from 1 to 12 ethylene glycol residues.
 18. Thecompound of claim 1, wherein the linker is a linker according to thechemical structure:

or a polypropylene glycol or polypropylene-co-polyethylene glycol linkercontaining between 1 and 100 alkylene glycol units; wherein R_(a) is H,C₁-C₃ alkyl or alkanol or forms a cyclic ring with R³ to form apyrrolidine or hydroxypyrroline group and R³ is a side chain derivedfrom a D- or L amino acid selected from the group consisting of alanine(methyl), arginine (propyleneguanidine), asparagine(methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol,reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamicacid (propanoic acid), glycine (H), histidine (methyleneimidazole),isoleucine (1-methylpropane), leucine (2-methylpropane), lysine(butyleneamine), methionine (ethylmethylthioether), phenylalanine(benzyl), proline, hydroxyproline (R³ forms a cyclic ring with R_(a) andthe adjacent nitrogen group to form a pyrrolidine or hydroxypyrrolidinegroup), serine (methanol), threonine (ethanol, 1-hydroxyethane),tryptophan (methyleneindole), tyrosine (methylene phenol) or valine(isopropyl); and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or15.
 19. The compound of claim 1, wherein the linker is a group accordingto the chemical structure:

wherein: R_(am) is H or C₁-C₃ alkyl optionally substituted with one ortwo hydroxyl groups; na is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, or 15; and m is an integer ranging from 1 to 100; or wherein thelinker is a group according to the chemical formula:

wherein: Z and Z′ are each independently a bond, —(CH₂)_(i)—O—,—(CH₂)_(i)—S—, —(CH₂)_(i)—N(R)—,

wherein the —(CH₂)_(i) group, if present in Z or Z′, is bonded to aconnector group [CON], [MIFBM]/[IgGBM] or [ASGPRBM]; each R is H, orC₁-C₃ alkyl or alkanol; each R² is independently H or C₁-C₃ alkyl; eachY is independently a bond, O, S, or N—R; each i is independently 0 to100; D is

or a bond, with the proviso that Z, Z′ and D are not each simultaneouslybonds; j is an integer ranging from 1 to 100; m′ is an integer rangingfrom 1 to 100; n is an integer ranging from 1 to 100; X¹ is O, S, orN—R; and R is H, C₁-C₃ alkyl, or alkanol.
 20. The compound of claim 1,wherein the linker is or comprises a group according to the chemicalstructure:

wherein each n and n′ is independently an integer ranging from 1 to 25;and each n″ is independently an integer ranging from 0 to 8; or whereinthe linker is a group represented by the chemical formula:PEG-[CON]-PEG wherein each PEG is independently a polyethylene glycolgroup containing from 1-12 ethylene glycol residues and [CON] is atriazole group


21. The compound of claim 1, wherein the [CON] is a group according tothe structure:

wherein R^(CON1) and R^(CON2) are each independently H, methyl, a bond(for attachment to another moiety); or a diamide group according to thestructure:

wherein: X² is CH₂, O, S, NR⁴, C(O), S(O), S(O)₂, —S(O)₂O, —OS(O)₂, orOS(O)₂O; X³ is O, S, or NR⁴; R⁴ is H, C₁-C₃ alkyl or alkanol, or—C(O)(C₁-C₃ alkyl); R¹ is H or C₁-C₃ alkyl; and n″ is independently 0,1, 2, 3, 4, 5, 6, 7, or 8; or the [CON] is a group according to thechemical structure:

wherein R^(1CON), R^(2CON), and R^(3CON) are each independently H,—(CH₂)_(MC1)—, —(CH₂)_(MC1a)C(O)_(XA)(NR⁴)_(XA)—(CH₂)_(MC1a)—,—(CH₂)_(MC1a)(NR⁴)_(XA)C(O)_(XA)—(CH₂)_(MC1a)—, or—(CH₂)_(MC1a)O—(CH₂)_(MC1)—C(O)NR⁴—, with the proviso that R^(1CON),R^(2CON) and R^(3CON) are not simultaneously H; each MC1 isindependently 0, 1, 2, 3, or 4; each MC1a is independently 0, 1, 2, 3,or 4; each XA is 0 or 1; and R⁴ is H, C₁-C₃ alkyl or alkanol, or—C(O)(C₁-C₃ alkyl), with the proviso that MC1a and XA in a moiety arenot all simultaneously
 0. 22. The compound of claim 1, wherein the [CON]is a group according to the chemical structure:


23. A compound selected from the group consisting of:

or a salt, stereoisomer, or solvate thereof.
 24. The compound of claim1, which is MIF-NVS-PEGnGN3, MIFGN3, MIF-PEGnGN3, MIF-CF₃-1, MIF-CF₃-2,MIF-CF₃-3, MIF-GN₃, MIF-AcF2, MIF-AcF3, MIF-AcF2-3, MIF-AcF3-2.MIF-AcF3-3, MIF-Ac-3, MIF-Et-3, MIF-EtF3-3, MIF-AcF, MIF-AcF-2,MIF-AcF-3, MIF-AcF2-2, MIF-Ac, MIF-Ac-2, MIF-Et, MIF-Et-2, MIF-EtF3, orMIF-EtF3-2.
 25. The compound of claim 1, having one of the followingformulae:

or a pharmaceutically acceptable salt thereof wherein: ExtracellularProtein Targeting Ligand is MIF or IgG Binding Moiety [MIFBM/IgGBM]which binds respectively to circulating MIF or IgG in a subject, each ofwhich is related to a disease state or condition and is to be removed byaction of hepatocytes or other cells of the subject; X¹ is 1 to 5 groupsindependently selected from O, S, N(R⁶), and C(R⁴)(R⁴), wherein if X¹ is1 group then X¹ is O, S, N(R⁶), or C(R⁴)(R⁴), if X¹ is 2 groups then nomore than 1 group of X¹ is O, S, or N(R⁶), if X¹ is 3, 4, or 5 groupsthen no more than 2 groups of X¹ are O, S, or N(R⁶), R² is selected from(i) aryl, heterocycle, and heteroaryl containing 1 or 2 heteroatomsindependently selected from N, O, and S, each of which aryl,heterocycle, and heteroaryl is optionally substituted with 1, 2, 3, or 4substituents; (ii)

(iii) —NR⁸—S(O)—R³, —NR⁸—C(S)—R³, —NR⁸—S(O)(NR⁶)—R³, —N═S(O)(R³)₂,—NR⁸C(O)NR⁹S(O)₂R³, —NR⁸—S(O)²—R¹⁰, and —NR⁸—C(NR⁶)—R³ each of which isoptionally substituted with 1, 2, 3, or 4 substituents, and (iv)hydrogen, R¹⁰, alkyl-C(O)—R³, —C(O)—R³, alkyl, haloalkyl, —OC(O)R³, and—NR⁸—C(O)R¹⁰; R¹⁰ is selected from aryl, alkyl-NR⁸—C(O)—R³, alkyl-aryl,alkyl-heteroaryl with 1, 2, or 4 heteroatoms, alkyl-cyano, alkyl-OR⁶,alkyl-NR⁶R⁸, NR⁸—NR⁶—C(O)R³, NR⁸—S(O)₂—R³, alkenyl, allyl, alkynyl,—NR⁶-alkenyl, —O-alkenyl, —NR⁶-alkynyl, —NR⁶-heteroaryl, —NR⁶-aryl,—O-heteroaryl, —O-aryl, and —O-alkynyl, each of which R¹⁰ is optionallysubstituted with 1, 2, 3, or 4 substituents; R¹ and R⁵ are independentlyselected from hydrogen, heteroalkyl, C₀-C₆alkyl-cyano, alkyl, alkenyl,alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocycle, heterocycloalkyl, haloalkoxy, —O-alkenyl,—O-alkynyl, C₀-C₆alkyl-OR⁶, C₀-C₆alkyl-SR⁶, C₀-C₆alkyl-NR⁶R⁷,C₀-C₆alkyl-C(O)R³, C₀-C₆alkyl-S(O)R³, C₀-C₆alkyl-C(S)R³,C₀-C₆alkyl-S(O)R⁶, C₀-C₆alkyl-N(R⁸)—C(O)R³, C₀-C₆alkyl-N(R⁸)—S(O)R³,C₀-C₆alkyl-N(R⁸)—C(S)R³, C₀-C₆alkyl-N(R⁸)—S(O)₂R³ C₀-C₆alkyl-O—C(O)R³,C₀-C₆alkyl-O—S(O)R³, C₀-C₆alkyl-O—C(S)R³, —N═S(O)(R³)₂, C₀-C₆alkylN₃,and C₀-C₆alkyl-O—S(O)₂R³, each of which is optionally substituted with1, 2, 3, or 4 substituents; R³ at each occurrence is independentlyselected from hydrogen, alkyl, heteroalkyl, haloalkyl (including —CF₃,—CHF₂, —CH₂F, —CH₂CF₃, —CH₂CH₂F, and —CF₂CF₃), arylalkyl,heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, —OR⁸,and —NR⁸R⁹; R⁴ is independently selected at each occurrence fromhydrogen, heteroalkyl, alkyl haloalkyl, arylalkyl, heteroarylalkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocycle, —OR⁶, —NR⁶R⁷, C(O)R³,S(O)R³, C(S)R³, and S(O)₂R³; R⁶ and R⁷ are independently selected ateach occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl,heteroarylalkyl, alkenyl, alkynyl, aryl, haloalkyl, heteroaryl,heterocycle, -alkyl-OR⁸, -alkyl-NR⁸R⁹, C(O)R³, S(O)R³, C(S)R³, andS(O)₂R³; R⁸ and R⁹ are independently selected at each occurrence fromhydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocycle; Cycle is a 3-8 memberedfused cyclic group optionally substituted with 1, 2, 3, or 4substituents; each Linker^(A) is a bond or a moiety that covalentlylinks the ASGPR ligand to Linker^(B); Linker^(B) is a bond or a moietythat covalently links Linker^(A) to an Extracellular Protein TargetingLigand; Linker^(C) is a chemical group that links each Linker^(A) to theExtracellular Protein Targeting Ligand; and Linker^(D) is a chemicalgroup that links each Linker^(A) to the Extracellular Protein TargetingLigand; and wherein, when R² is NR⁶-alkenyl, —NR⁶-alkynyl, —NR⁸—C(O)R¹⁰,—NR⁸—S(O)₂-alkenyl, —NR⁸—S(O)₂-alkynyl, —NR₆-heteroaryl, or —NR⁶-aryl,then Extracellular Protein Targeting Ligand does not comprise anoligonucleotide; and the optional substituents are selected from alkyl,alkenyl, alkynyl, haloalkyl, —OR⁶, F, Cl, Br, I, —NR⁶R⁷, heteroalkyl,cyano, nitro, C(O)R³,

as allowed by valence such that a stable compound results.
 26. Apharmaceutical composition comprising an effective amount of a compoundof claim 1 in combination with a pharmaceutically acceptable carrier,additive, or excipient, optionally further comprising an additionalbioactive agent effective to treat cancer, autoimmune disease,inflammatory disease, or a disease or disorder which is associated withthe upregulation of MIF or IgG in the patient or subject.
 27. Thecomposition of claim 26, wherein the additional anticancer agent isselected from the group consisting of: everolimus, trabectedin,abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152,enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763,AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, anaurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an HDACinhibitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFRTK inhibitor, an IGFR TK inhibitor, an anti-HGF antibody, a PI3 kinaseinhibitors, an AKT inhibitor, a JAK/STAT inhibitor, a checkpoint-1 or 2inhibitor, a focal adhesion kinase inhibitor, a Map kinase kinase (mek)inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib,nilotinib, decatanib, panitununab, amrubicin, oregovomab, Lep-etu,nolatrexed, azd2171, batabulin, ofatumumab (Arzerra), zanolimumab,edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen,ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR₁KRX-0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102,talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib,5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin,irinotecan, liposomal doxorubicin, 5′-deoxy-5-fluorouridine,vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244,capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-,disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258);3-[5-(methylsulfonylpiperadinemethyl)-indolylj-quinolone, vatalanib,AG-013736, AVE-0005, the acetate salt of [D-Ser(Bu t) 6,Azgly 10](pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu t)-Leu-Arg-Pro-Azgly-NH₂ acetate[C₅₉H₈₄N₁₈Oi₄-(C₂H₄O₂)_(X) where x=1 to 2.4], goserelin acetate,leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate,hydroxyprogesterone caproate, megestrol acetate, raloxifene,bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714;TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody,erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662,tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid,valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951,aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, BacillusCalmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan,carboplatin, carmustine, chlorambucil, cisplatin, cladribine,clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin,daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox, gefitinib, bortezimib, paclitaxel, irinotecan,topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab, erbitux,cremophor-free paclitaxel, epithilone B, BMS-247550, BMS-310705,droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene,fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339,ZK186619, PTK787/ZK 222584, VX-745, PD 184352, rapamycin,40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonists,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin,epoetin alfa and darbepoetin alfa, vemurafenib, immunotherapy agentsPDL1 inhibitors, PD1 inhibitors, or CTLA-4 inhibitors.
 28. A method ofremoving excess circulating MIF or IgG in a patient or subject, ortreating a disease state or condition which is associated with theupregulation of MIF or IgG in a patient or subject, the methodcomprising administering to the patient or subject an effective amountof a compound of claim
 1. 29. The method of claim 28, wherein thedisease state or condition is cancer, an autoimmune disease, or aninflammatory disease.
 30. A method of treating, ameliorating, orpreventing cancer, an autoimmune disease, or an inflammatory disease ina subject or patient, the method comprising administering to the subjector patient a therapeutically effective amount of a compound of claim 25.